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Dopamine and Parkinson's disease

(152 References)

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(2002). "[In Process Citation]." Ross Fiziol Zh Im I M Sechenova 88(2): 144-57.
A possible mechanism of cannabinoid-mediated akinesia is suggested. This effect is proposed to be the consequence of a decrease in LTD/LTP in cortical inputs to striatopallidal/striatonigral cells in the matrix due to CB1 receptor activation. In addition, cannabinoids can attenuate locomotor activity due to a reducing of glutamate/GABA release from axon terminals of subthalamic nucleus/striatonigral cells of matrix and subsequent decrease/increase in the activity of neurons of globus pallidus/substantia nigra pars reticulata. Cannabinoid-mediated rise of dopamine release might be a result of a decrease of dopamine neuron inhibition by striatonigral cells of striosomes. It follows from the suggested mechanism that an inactivation (activation) of CB1 receptors leading to rise (lowering) of the motor activity can be useful for treatment of Parkinson (Huntington) disease.

Akaike, A., H. Katsuki, et al. (2002). "[Role of nitric oxide in survival and death of neurons]." Nippon Yakurigaku Zasshi 119(1): 15-20.
The prominent pathological feature of the brain in Parkinson's disease is selective degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Glutamate and nitric oxide (NO) are the major effectors of the radical stress that may induce selective loss of dopaminergic neurons. It has been postulated that neurotoxicity induced by glutamate and NO in dopaminergic neurons is regulated by certain endogenous factors. We have reported that estradiol protects dopaminergic neurons against NO-mediated glutamate neurotoxicity by reducing intracellular reactive oxygen species (ROS) levels. We further searched for a candidate for neuroprotective substances with unique structure. From the ether extract of fetal calf serum (FCS), we isolated a novel substance possessing protective activity against neurotoxicity induced by glutamate NO. The compound was a sulfur-containing diterpenoid and showed hydroxyl radical scavenging activity. We further analyzed the change of resistance to excitotoxicity in midbrain dopaminergic neurons in co-culture with the striatum by using a slice culture technique. The results suggested that the generation of NO is involved in NMDA cytotoxicity on dopaminergic neurons and that increased activity of SOD in co-culture renders dopaminergic neurons resistant to NMDA cytotoxicity by preventing peroxynitrite formation. Those findings suggest that regulation of intracellular ROS levels plays a critical role in protecting neurons against NO-mediated radical stress in neurodegenerative disorders.

Arnulf, I., E. Konofal, et al. (2002). "Parkinson's disease and sleepiness: an integral part of PD." Neurology 58(7): 1019-24.
OBJECTIVE: To investigate the potential causes of excessive daytime sleepiness in patients with PD-poor sleep quality, abnormal sleep-wakefulness control, and treatment with dopaminergic agents. METHODS: The authors performed night-time polysomnography and daytime multiple sleep latency tests in 54 consecutive levodopa-treated patients with PD referred for sleepiness, 27 of whom were also receiving dopaminergic agonists. RESULTS: Sleep latency was 6.3 +/- 0.6 minutes (normal >8 minutes), and the Epworth Sleepiness score was 14.3 +/- 4.1 (normal <10). A narcolepsy-like phenotype (> or = 2 sleep-onset REM periods) was found in 39% of the patients, who were sleepier (4.6 +/- 0.9 minutes) than the other 61% of patients (7.4 +/- 0.7 minutes). Periodic leg movement syndromes were rare (15%, range 16 to 43/h), but obstructive sleep apnea-hypopnea syndromes were frequent (20% of patients had an apnea-hypopnea index >15/h; range 15.1 to 50.0). Severity of sleepiness was weakly correlated with Epworth Sleepiness score (r = -0.34) and daily dose of levodopa (r = 0.30) but not with dopamine-agonist treatment, age, disease duration, parkinsonian motor disability, total sleep time, periodic leg movement, apnea-hypopnea, or arousal indices. CONCLUSIONS: In patients with PD preselected for sleepiness, severity of sleepiness was not dependent on nocturnal sleep abnormalities, motor and cognitive impairment, or antiparkinsonian treatment. The results suggest that sleepiness-sudden onset of sleep-does not result from pharmacotherapy but is related to the pathology of PD.

Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen 122(5): 525-9.
BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical symptoms, pharmacological and nonpharmacological treatment, based on the literature and on personal experience. RESULTS: Neurochemical findings are marked cortical reduction of acetylcholine and nigrostriatal dopamine deficiency. Key features of the clinical syndrome are dementia, fluctuating consciousness, visual hallucinations and parkinsonism. There are pathological and clinical overlaps between DLB and Alzheimer's disease on the one hand, and between DLB and Parkinson's disease on the other; the relationship between these diseases awaits further elucidation. Clinical consensus criteria for DLB have been published and shown to have high sensitivity and specificity. Fluctuating consciousness may be difficult to detect, but diagnostic instruments exist that may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase inhibitors have been shown to improve cognition and psychiatric symptoms. Atypical antipsychotics may improve psychosis, but some patients develop severe sensitivity reactions. The effect of antiparkinson agents is unknown.

Auluck, P. K., H. Y. Chan, et al. (2002). "Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease." Science 295(5556): 865-8.
Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha-synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.

Balachandran, K. P., D. Stewart, et al. (2002). "Chronic pericardial constriction linked to the antiparkinsonian dopamine agonist pergolide." Postgrad Med J 78(915): 49-50.
Constrictive pericarditis is present when a fibrotic, thickened, and adherent pericardium restricts diastolic filling of the heart. Several drugs can cause pericarditis, which can lead to chronic pericardial constriction. A case of constrictive pericarditis in a patient receiving the antiparkinsonian drug pergolide is reported.

Battaglia, G., C. L. Busceti, et al. (2002). "Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice." Neuropharmacology 42(3): 367-73.
Apomorphine has been introduced in the treatment of late-stage Parkinson's Disease (PD). The disadvantage of a short half-life of apomorphine is now overcome by the use of a continuous subcutaneous (s.c.) self-delivering system. We examined whether continuous s.c. infusion of apomorphine rescues nigro-striatal dopaminergic neurons from toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Apomorphine was continuously infused in mice by means of a s.c. minipump that delivered the drug at a rate of 0.5 or 3.15mg/kg/day. MPTP induced a >80% reduction in striatal dopamine (DA) after one day. DA levels were still substantially reduced one month following MPTP injection, in spite of a partial recovery. Similarly, striatal immunoreactivity for tyrosine hydroxylase and dopamine transporter was markedly reduced at this time interval. Continuous s.c. infusion of apomorphine starting 40h following MPTP injection rescued striatal dopaminergic terminals, as assessed by measurements of DA and its metabolites, as well as TH and DAT immunostaining after one month. The neurorescuing effect was more remarkable at a delivery rate of 3.15mg/kg/day of apomorphine. In contrast, no rescue was observed when apomorphine was administered as a single daily s.c. bolus of 1 or 5mg/kg starting 40h following MPTP. We conclude that apomorphine is able to rescue nigro-striatal dopaminergic neurons when continuously delivered at doses that are comparable to those delivered by minipumps in PD patients. These results suggest that continuous s.c. infusion of apomorphine not only relieves the symptoms, but also reduce the ongoing degeneration of nigro-striatal dopaminergic neurons in PD patients.

Bergman, H. and G. Deuschl (2002). "Pathophysiology of Parkinson's disease: From clinical neurology to basic neuroscience and back." Mov Disord 17 Suppl 3: S28-40.
Parkinson's disease (PD) is characterized by motor and nonmotor (cognitive and limbic) deficits. The motor signs of PD include hypokinetic signs such as akinesia/bradykinesia, rigidity and loss of normal postural reflexes, and hyperkinetic signs such as tremor. Dopamine depletion in the striatum is the hallmark of PD and of its animal models, still the pathophysiology of the parkinsonian symptoms and especially of parkinsonian tremor are under debate. The most extreme hypotheses argue about peripheral versus central nervous system origin, intrinsic cellular oscillator versus network oscillators, and basal ganglia-based pathophysiology versus cerebellar-thalamic based pathophysiology. Recent studies support the view that parkinsonian symptoms are most likely due to abnormal synchronous oscillating neuronal activity within the basal ganglia. Peripheral factors do only play a minor role for the generation, maintenance, and modulation of PD tremor and other signs. The most likely candidates producing these neuronal oscillations are the weakly coupled neural networks of the basal ganglia-thalamo-cortical loops. However, the present evidence supports the view that the basal ganglia loops are influenced by other neuronal structures and systems and that the tuning of these loops by cerebello-thalamic mechanisms and by other modulator neurotransmitter systems entrain the abnormal synchronized oscillations. Neurosurgical procedures, such as lesions or high-frequency stimulation of different parts of the loop, might resume the normal unsynchronized activity of the basal ganglia circuitry, and, therefore, ameliorate the clinical symptoms of Parkinson's disease.

Betarbet, R., T. B. Sherer, et al. (2002). "Animal models of Parkinson's disease." Bioessays 24(4): 308-18.
Animal models are important tools in experimental medical science to better understand pathogenesis of human diseases. Once developed, these models can be exploited to test therapeutic approaches for treating functional disturbances observed in the disease of interest. On the basis of experimental and clinical findings, Parkinson's disease (PD) was the first neurological disease to be modeled and, subsequently, to be treated by neurotransmitter replacement therapy. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have been used to develop PD models. Recently, it has been found that agricultural chemicals, such as rotenone and paraquat, when administered systemically, can reproduce specific features of PD in rodents, apparently via oxidative damage. Transgenic animals that over-express alpha-synuclein are used to study the role of this protein in dopaminergic degeneration. This review critically discusses animal models of PD and compares them with characteristics of the human disease.

Biglan, K. M. and R. G. Holloway (2002). "A review of pramipexole and its clinical utility in Parkinson's disease." Expert Opin Pharmacother 3(2): 197-210.
Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex((R)), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.

Bilsland, J., S. Roy, et al. (2002). "Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons." J Neurosci 22(7): 2637-49.
Parkinson's disease is characterized by a loss of dopaminergic nigrostriatal neurons. This neuronal loss is mimicked by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). MPP+ toxicity is mediated through inhibition of mitochondrial complex I, decreasing ATP production, and upregulation of oxygen radicals. There is evidence that the cell death induced by MPP+ is apoptotic and that inhibition of caspases may be neuroprotective. In primary cultures of rat mesencephalic dopaminergic neurons, MPP+ treatment decreased the number of surviving dopaminergic neurons in the cultures and the ability of the neurons to take up [3H]dopamine ([3H]DA). Caspase inhibition using the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) spared MPP+-treated dopaminergic neurons and increased somatic size. There was a partial restoration of neurite length in zVAD-fmk-treated cultures, but little restoration of [3H]DA uptake. Peptide inhibitors of caspases 2, 3, and 9, but not of caspase 1, caused significant neuroprotection. Two novel caspase inhibitors were tested for neuroprotection, a broad spectrum inhibitor and a selective caspase 3 inhibitor; both inhibitors increased survival to >90% of control. No neuroprotection was observed with an inactive control compound. MPP+ treatment caused chromatin condensation in dopaminergic neurons and increased expression of activated caspase 3. Inhibition of caspases with either zVAD-fmk or a selective caspase 3 inhibitor decreased the number of apoptotic profiles, but not expression of the active caspase. We conclude that MPP+ toxicity in primary dopaminergic neurons involves activation of a pathway terminating in caspase 3 activation, but that other mechanisms may underlie the neurite loss.

Bjorklund, L. M., R. Sanchez-Pernaute, et al. (2002). "Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model." Proc Natl Acad Sci U S A 99(4): 2344-9.
Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease.

Bonuccelli, U., A. Colzi, et al. (2002). "Pergolide in the treatment of patients with early and advanced Parkinson's disease." Clin Neuropharmacol 25(1): 1-10.
SUMMARY: Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.

Boraud, T., E. Bezard, et al. (2002). "From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control." Prog Neurobiol 66(4): 265-83.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects the whole basal ganglia (BG). Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. An impressive number of studies of BG electrophysiological activity have been carried out, both in non-human and in human primates, but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation, but remains far from clear in the Parkinsonian and virtually unexplored in the dopamine (DA)-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. Then, the main successive theories aimed to explain the role played by BG in motor control are presented and discussed in the light of the most recently obtained results using the latest technological advances.

Bringmann, G., D. Feineis, et al. (2002). "1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis." Bioorg Med Chem 10(7): 2207-2214.
1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 2) is a mammalian alkaloid that readily originates in the human organism, by Pictet-Spengler condensation of endogenously present tryptamine (Ta) and the non-natural hypnotic agent trichloroacetaldehyde (chloral, Clo). Due to its structural analogy to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1), TaClo is discussed to possibly contribute to the pathogenesis of Parkinson's disease acting as an environmental toxin. Previous investigations on rats and neuronal cell cultures revealed 2 to be capable of inducing severe disturbances on the dopamine metabolism. In this paper, we report on the effects of 2 on the activity of tyrosine hydroxylase [L-tyrosine, tetrayhydropteridine/oxygen oxidoreductase (3-hydroxylating), EC 1.14,16.2; TH] in vitro using rat brain homogenates prepared from the TH-rich nucleus accumbens. TaClo (2) dose-dependently inhibited basal TH activity (IC(50)=3&mgr;M), and after enzyme activation by pituitary adenylate cyclase-activating polypeptide (PACAP-27), it also reduced L-DOPA formation (IC(50)=15&mgr;M). Moreover, two presumable TaClo metabolites, 2-methyl-TaClo (N-Me-TaClo, 3) and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2)-THbetaC, 4), which were synthesized in good yields, also proved to be potent inhibitors of TH, with the strongest effect on basal activity (similar to TaClo) being observed for 3 (IC(50)=3&mgr;M). In contrast to TaClo, however, 3 and 4 showed biphasic effects after TH activation with PACAP-27, inducing a marked increase of enzyme activity in the nanomolar range (<0.1&mgr;M), while TH activity was nearly completely blocked at high concentrations (IC(100)=0.1mM). An X-ray diffraction investigation on the 3-dimensional structure of the 1-CCl(2)-THbetaC-derived trifluoroacetamide 7 revealed the voluminous and quite rigid dichloromethylene substituent to be only moderately twisted out of the beta-carboline ring 'plane', thus resulting in an inreased ring strain of the partially hydrogenated pyrido moiety accompanied by a strong steric hindrance of Cl(1), Cl(2), C(13), and N(2), which pushes the N-trifluoroacetyl group upwards to an even higher extent than for the TaClo-related trifluoroacetamide 8.

Brunt, E. R., D. J. Brooks, et al. (2002). "A six-month multicentre, double-blind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by l-dopa." J Neural Transm 109(4): 489-501.
SUMMARY: OBJECTIVES: To compare the safety and efficacy of ropinirole and bromocriptine as adjunct therapy in patients with Parkinson's disease (PD) not optimally controlled by L-dopa. METHODS: A randomised, double-blind trial in which 555 patients were assigned to three treatment groups according to the level of daily dosage of L-dopa, presence of motor fluctuations, and use of dopamine agonist before study entry. Patient response was defined as at least a 20% reduction in daily L-dopa dose plus: for patients with no prior treatment and no motor fluctuations, a 20% reduction in UPDRS motor score; for patients with motor fluctuations, a 20% reduction in time spent "off"; and for patients already taking an agonist, an improvement on the CGI scale. RESULTS: Safety assessments showed no significant differences in the two treatment groups for patients without prior dopamine-agonist therapy. In the group of patients with prior dopamine-agonist therapy, more patients reported adverse events in the ropinirole group (90% versus 79%, p < 0.001). The proportions of responders tended to be higher in ropinirole groups compared with bromocriptine groups and, in the subgroup with motor fluc-tuations, this difference was statistically significant (9.1% versus 0.0%, respectively; p < 0.05). CONCLUSIONS: Both drugs were well tolerated. In patients receiving a relatively high dose of L-dopa and requiring the addition of a dopamine agonist to control motor fluctuations or dyskinesias, ropinirole was significantly more effective than bromocriptine.

Callier, S., M. Le Saux, et al. (2002). "Evaluation of the protective effect of oestradiol against toxicity induced by 6-hydroxydopamine and 1-methyl-4-phenylpyridinium ion (Mpp+) towards dopaminergic mesencephalic neurones in primary culture." J Neurochem 80(2): 307-16.
Recent findings suggest that gonadal steroid hormones are neuroprotective and may provide clinical benefits in delaying the development of Parkinson's disease. In this report we investigated the ability of oestradiol to protect mesencephalic dopaminergic neurones cultured in serum-free or serum-supplemented medium from toxicity induced by 6-hydroxydopamine or 1-methyl-4-phenylpyridinium ion (MPP+). The efficiency of both toxins and oestradiol was evaluated by tyrosine hydroxylase (TH) immunocytochemistry, [3H]dopamine ([3H]DA) uptake, length of dopaminergic processes and lactate dehydrogenase (LDH) release measurement. In cultures grown in serum-supplemented medium, a 2-h pre-treatment with high concentrations (10-100 microM) of 17beta-oestradiol or 17alpha-oestradiol, the stereoisomer with weak oestrogenic activity, protected both dopaminergic and non-dopaminergic neurones from toxicity induced by 6-hydroxydopamine (6-OHDA; 40 or 100 microM) and by the high MPP+ concentrations (50 microM) necessary to obtain significant neuronal death under those culture conditions. At these concentrations, MPP+ was no longer selective for dopaminergic neurones but affected all cells present in the culture. In contrast, the hormonal treatments did not protect against selective degeneration of dopaminergic neurones induced by lower MPP+ concentrations (below 10 microM), related to inhibition of complex I of respiratory chain. In cultures grown in serum-free medium, oestradiol concentrations higher than 1 microM induced neuronal degeneration and no protection against 6-OHDA or MPP+ toxicity was observed at lower concentrations of the steroid. The neuroprotective effects of 17alpha- or 17beta-oestradiol evidenced in this model might be due to the antioxidant properties of these compounds. However, other non-genomic effects of the steroids cannot be excluded.

Calon, F., S. Birdi, et al. (2002). "Increase of preproenkephalin mRNA levels in the putamen of Parkinson disease patients with levodopa-induced dyskinesias." J Neuropathol Exp Neurol 61(2): 186-96.
The expression of preproenkephalin messenger RNA was studied in the brain of Parkinson disease (PD) patients using in situ hybridization. All these patients were treated with levodopa (LD) and the development of motor complications was recorded. Eleven normal controls and 14 PD patients were used, of which 4 developed dyskinesias, 3 developed wearing-off, 3 developed both dyskinesias and wearing-off, and 4 developed no adverse effect following dopaminomimetic therapy. Nigrostriatal denervation was similar between the subgroups of PD patients as assessed using 125I-RTI-specific binding to the dopamine transporter and measures of catecholamine concentrations by HPLC. A significant increase of preproenkephalin messenger RNA levels was observed in the lateral putamen of dyskinetic patients in comparison to controls (+210%; p < 0.01) and in comparison to nondyskinetic patients (+112%; p < 0.05). No change was observed in medial parts of the putamen or in the caudate nucleus. No relationship between preproenkephalin messenger RNA levels and other clinical variables such as development of wearing-off, age of death, duration of disease, or duration of LD therapy was found. These findings suggest that increase synthesis of preproenkephalin in the medium spiny output neurons of the striatopallidal pathway play a role in the development of dyskinesias following long-term LD therapy in Parkinson disease.

Calon, F., M. Morissette, et al. (2002). "Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment." Prog Neuropsychopharmacol Biol Psychiatry 26(1): 127-38.
The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal lesion and dopaminomimetic treatment on parameters of glutamatergic activity within the basal ganglia of monkeys were studied in relation with the development of dyskinesias. Drug-naive controls, saline-treated MPTP monkeys, as well as MPTP monkeys treated with either a long-acting D2 agonist (cabergoline) or a D1 agonist (SKF-82958) given by intermittent injections or continuous infusion, were included in this study. 3H-L-glutamate, 3H-alpha-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA), 3H-glycine, 3H-CGP39653 (an N-methyl-D-aspartate, NMDA, antagonist selective for NR1/NR2A assembly) and 3H-Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly), specific binding to glutamate receptors, the expression of the NR1 subunit of NMDA receptors and glutamate, glutamine and glycine concentrations were studied by autoradiography, in situ hybridization and high-performance liquid chromatography (HPLC), respectively. Pulsatile SKF-82958 and cabergoline treatment relieved parkinsonian symptoms, whereas animals continuously treated with SKF-82958 remained akinetic. Pulsatile SKF-82958 induced dyskinesias in two of the three animals tested, whereas cabergoline did not. MPTP induced no significant changes of striatal specific binding of the radioligands used, NR1 mRNA expression and amino acid concentrations. In the putamen, pulsatile SKF-82958 treatment was associated with decreased content of glycine and glutamate, whereas only glycine was decreased in cabergoline-treated monkeys. Cabergoline and continuous administration of SKF-82958 led to lower levels of NR1 mRNA in the caudate in comparison to pulsatile SKF-82958 administration. The development of dyskinesias following a D1 agonist treatment was associated with an upregulation of 3H-glutamate [+49%], 3H-AMPA [+38%], 3H-CGP39653 [+ 111%], 3H-glycine [+ 26%, nonsignificant] and 3H-Ro 25-6981 [+ 33%] specific binding in the striatum in comparison to nondyskinetic MPTP monkeys. Our data suggest that supersensitivity to glutamatergic input in the striatum might play a role in the pathogenesis of dopaminomimetic-induced dyskinesias and further support the therapeutic potential of glutamate antagonists in Parkinson's disease.

Cantello, R., R. Tarletti, et al. (2002). "Transcranial magnetic stimulation and Parkinson's disease." Brain Res Brain Res Rev 38(3): 309-27.
While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson's disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at 'rest', or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed 'central silent period', which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABA(B) receptors. The so-called 'short-interval intracortical inhibition', which is possibly mediated by GABA(A) receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.

Cantor, C. R. and M. B. Stern (2002). "Dopamine agonists and sleep in Parkinson's disease." Neurology 58(4 Suppl 1): S71-8.
Dopaminergic therapy is increasingly recognized as a cause of excessive daytime sleepiness in patients with PD. This adverse effect may be a dose-related phenomenon that is somewhat more likely to occur with dopamine agonists than with levodopa, although all dopaminergic drugs can be sedating. However, medication effect is only one of several causes of somnolence in PD. Other factors include age-related changes in sleep quality, nocturnal motor disturbances, primary sleep disorders such as sleep apnea, medication-induced sleep disruption, and concurrent medical illnesses. There is also increasing evidence that the disease process itself may affect the control of the sleep-wake cycle. Although we have characterized the sleep disturbances in PD, further investigation is needed to define their prevalence and etiology, particularly with respect to the role of dopamine and dopaminergic agents. Clinicians should be alert to the complaint of excessive sleepiness in their patients and should attempt to identify and treat the underlying causes.

Carta, A. R., A. Pinna, et al. (2002). "Differential regulation of GAD67, enkephalin and dynorphin mRNAs by chronic-intermittent L-dopa and A(2A) receptor blockade plus L-Dopa in dopamine-denervated rats." Synapse 44(3): 166-74.
Adenosine A(2A) receptor antagonists have been proposed as an effective therapy in the treatment of Parkinson's disease. In the present study, we compared the modifications on striatal glutamate decarboxylase (GAD67), enkephalin, and dynorphin mRNA levels produced by a chronic-intermittent administration of L-3,4-dihydroxyphenyl-alanine (L-dopa) (6 mg/kg) with those produced by the adenosine A(2A) receptor antagonist SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. As previously reported, L-dopa (6 mg/kg) and SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced the same degree of turning behavior after the first administration. However, while L-dopa (6 mg/kg) induced a sensitized turning behavior response during the course of the treatment, which indicated a dyskinetic potential, SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced a stable turning behavior response, which was predictive of absence of dyskinetic side effects. Unilateral 6-OHDA lesion produced an elevation in striatal GAD67 and enkephalin mRNA levels and to a decrease in dynorphin mRNA levels. Chronic-intermittent L-dopa (6 mg/kg) treatment increased the striatal levels of GAD67, dynorphin, and enkephalin mRNA in the lesioned side as compared to the vehicle treatment. Chronic-intermittent SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) as well as L-dopa (3 mg/kg) or SCH 58261 (5 mg/kg) alone did not produce any significant modification in GAD67, dynorphin, or enkephalin mRNA levels in the lesioned striatum as compared to the striatum of vehicle-treated rats. The results show that combined SCH 58261 plus L-dopa did not produce long-term changes in markers of striatal efferent neurons activity and suggest that the lack of modifications in GAD67 and dynorphin mRNA after SCH 58261 plus L-dopa might correlate with the lack of turning behavior sensitization which predicts drug dyskinetic potential.

Ceravolo, R., P. Piccini, et al. (2002). "18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease." Synapse 43(3): 201-7.
Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Cesati, R. R., 3rd, G. Tamagnan, et al. (2002). "Synthesis of cyclopentadienyltricarbonyl rhenium phenyltropanes by double ligand transfer: organometallic ligands for the dopamine transporter." Bioconjug Chem 13(1): 29-39.
Cyclopentadienyltricarbonyl rhenium (CpRe(CO)(3)) systems can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction that gives reasonable yields and shows excellent functional group tolerance. We used this reaction for the direct preparation of CpRe(CO)(3)-phenyltropane conjugates. Such agents, when labeled with technetium-99m, might function as imaging agents for the dopamine transporter (DAT) system that would be useful for assessing the onset and severity of Parkinson's disease. Of the CpRe(CO)(3)-tropane conjugates prepared by the DLT reaction (as well as other analogues prepared by related methods), those substituted at the N-8 position seem most promising; their affinity for the DAT in all cases was high, and their ferrocene precursors for the DLT reaction can be prepared in a convenient manner. By contrast, the 3 beta-conjugates were poor DAT binders. The modular nature of these systems offers considerable flexibility that could be used to improve the binding characteristics of these compounds further.

Chen, B. T., M. V. Avshalumov, et al. (2002). "Modulation of somatodendritic dopamine release by endogenous H(2)O(2): susceptibility in substantia nigra but resistance in VTA." J Neurophysiol 87(2): 1155-8.
We showed previously that dopamine (DA) release in dorsal striatum is inhibited by endogenously generated hydrogen peroxide (H(2)O(2)). Here, we examined whether endogenous H(2)O(2) can also modulate somatodendritic DA release in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), with companion measurements in DA terminal regions. Evoked DA release was monitored in brain slices using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Exogenous H(2)O(2) decreased DA release by 50-60% in SNc and VTA but only by 35% in nucleus accumbens. Whether endogenous H(2)O(2) also modulated somatodendritic release was examined using the glutathione peroxidase inhibitor, mercaptosuccinate (MCS), which should increase stimulation-evoked H(2)O(2) levels. In the presence of MCS, DA release was suppressed by 30-40% in SNc as well as in dorsal striatum and nucleus accumbens. In striking contrast, DA release in the VTA was unaffected by MCS. These data are consistent with stronger H(2)O(2) regulation or lower H(2)O(2) generation in VTA than in the other regions. Importantly, oxidative stress has been linked causally to Parkinson's disease, in which DA cells in SNc degenerate, but VTA cells are spared. The present data suggest that differences in oxidant regulation or generation between SNc and VTA could contribute to this.

Chen, L. W., L. C. Wei, et al. (2002). "Significant up-regulation of nestin protein in the neostriatum of MPTP-treated mice. Are the striatal astrocytes regionally activated after systemic MPTP administration?" Brain Res 925(1): 9-17.
We are interested in the possible role of central glial cells in pathogenesis of Parkinson's disease of mammals. Parkinsonism model was induced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and the reactive glial cells were examined by immunocytochemical visualization of nestin protein in the brains and spinal cords of C57 mice. Abundant nestin-like immunoreactivity was predominately found in the caudate putamen of MPTP-treated mice and about 481-fold of nestin-like immunoreactive cells increased compared with that of control animals, indicating that significant up-regulation of nestin protein occurred in these regions. Majority of nestin-like immunoreactive cells characterized with astrocytic profiles of multiple, radical and hypotrophic processes, and showed a distribution and dynamic patterns similar to that of glial fibrillary acid protein (GFAP)-immunoreactive cells in the caudate putamen. Double immunofluorescence confirmed that 100% of nestin-like immunoreactive cells exhibited GFAP-immunoreactivity while nestin/GFAP double-labeled cells constituted about 84% of total GFAP-immunoreactive cells in the caudate putamen, indicating these nestin-like immunoreactive cells belong to a reactive population of the astrocytes. On the other hand, no obvious changes of nestin- or GFAP-like immunoreactivities were detected in the globus pallidus, the substantia nigra and the ventral tegmental area after MPTP-treatment. The results have provided morphological evidence for the regional activation of astrocytic glial cells following systemic MPTP administration, suggesting that a large population of reactive striatal astrocytes might play an important role in initial pathogenesis or acute stage of Parkinson's disease in mammals.

Chun, H. S., M. S. Yoo, et al. (2002). "Marked dopaminergic cell loss subsequent to developmental, intranigral expression of glial cell line-derived neurotrophic factor." Exp Neurol 173(2): 235-44.
Glial cell line-derived neurotrophic factor (GDNF) shows potent neuroprotective as well as neurorestorative actions on the adult neurons impacted in animal models of Parkinson's disease (PD). Long-term pharmaco-physiological effects of GDNF on developing dopaminergic (DA) neurons have not yet been explored because of technical difficulties in producing prolonged cell type-specific delivery of this neurotrophic factor in mammalian embryonic brain. The current studies used our previously characterized 9.0-kb tyrosine hydroxylase promoter to produce transgenic mice with neuronal cell type-specific expression of GDNF in substantia nigra pars compacta (SNc) and locus coeruleus (LC). These mice were used to test the parsimonious hypothesis that increased developmental expression of GDNF in SNc and LC would significantly enhance the number of postmitotic adult neurons. To our surprise, adult transgenic mice carrying the TH9.0kb-GDNF hybrid gene showed dramatic reductions in both the numbers and the volumes of SNc-DA and LC-noradrenergic (NA) neurons by quantitative morphometric analysis. The decrease in the number of DA neurons was apparent as early as postnatal day 2, the period before the major naturally occurring apoptotic cell death in midbrain. Aged transgenic mice exhibited no further significant deficits in motor behaviors. These data suggest that continuous, early developmental GDNF expression exerts physiological effects on newly differentiated, immature dopamine neurons that differ from those observed on more mature and adult DA neurons. Further elucidation of the mechanisms underlying differential GDNF actions will greatly improve the pharmacological efficacy of GDNF in fetal neural transplantation as well as adult neuronal gene therapy in PD patients.

Cicchetti, F., A. L. Brownell, et al. (2002). "Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging." Eur J Neurosci 15(6): 991-8.
We investigated the microglial response to progressive dopamine neuron degeneration using in vivo positron emission tomography (PET) imaging and postmortem analyses in a Parkinson's disease (PD) rat model induced by unilateral (right side) intrastriatal administration of 6-hydroxydopamine (6-OHDA). Degeneration of the dopamine system was monitored by PET imaging of presynaptic dopamine transporters using a specific ligand (11)C-CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane). Binding of (11)C-CFT was markedly reduced in the striatum indicating dopaminergic degeneration. Parallel PET studies of (11)C-PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinoline carboxamide) (specific ligand for activated microglia) showed increased binding in the striatum and substantia nigra indicative of a microglial response. Postmortem immunohistochemical analyses were performed with antibodies against CR3 for microglia/macrophage activation. Using a qualitative postmortem index for microglial activation we found an initially focal, then widespread microglial response at striatal and nigral levels at 4 weeks postlesion. These data support the hypothesis that inflammation is a significant component of progressive dopaminergic degeneration that can be monitored by PET imaging.

Clarke, C. E. (2002). "Medical management of Parkinson's disease." J Neurol Neurosurg Psychiatry 72 Suppl 1: I22-I27.

Collier, T. J., C. E. Sortwell, et al. (2002). "Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson's disease." J Comp Neurol 442(4): 320-30.
Transplantation of embryonic dopamine (DA) neurons is being studied as an experimental replacement therapy for the DA-deficiency characteristic of Parkinson's disease. Some studies suggest that one of the limitations of this approach is that intrastriatal placement of implants fails to consistently restore completely normal movement. One potential cause of this suboptimal therapeutic outcome is that changes in the neural activity of several structures in the basal ganglia circuitry resulting from striatal DA depletion is not adequately normalized by graft-derived DA replacement in striatum alone. In the present study, we assessed the feasibility of grafting embryonic DA neurons into the substantia nigra (SN) of adult parkinsonian monkeys as an approach to restoration of the DA modulation of striatal-nigral afferents that is lost after degeneration of SN neurons. Sixteen St. Kitts African green monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) received implants of embryonic monkey ventral mesencephalon (VM), or sham implants, aimed at the rostral SN. At 6 months after grafting, staining for tyrosine hydroxylase (TH) indicated that grafted DA neurons survived at this site, albeit often in reduced numbers compared with VM grafts to striatum. Grafted neurons extended neurites into the parenchyma of the SN, but there was no evidence of lengthy extension of graft-derived neurites rostrally along the trajectory of the mesostriatal fiber system. A region-specific, modest increase in DA levels and TH-positive fiber density in the ventral-medial putamen was detected, accompanied by modest but significant decreases in parkinsonian behaviors at 5-6 months after grafting. Our findings support the view that grafting embryonic tissue to the SN is a feasible procedure in nonhuman primates that provides a modest but detectable benefit of its own. These results encourage the further development of multiple-target grafting strategies as a means of restoring modulation of anatomically widespread basal ganglia structures relevant to treatment of Parkinson's disease.

Comella, C. L. (2002). "Daytime sleepiness, agonist therapy, and driving in Parkinson disease." Jama 287(4): 509-11.

Cools, A. R., L. Lubbers, et al. (2002). "SKF 83959 is an antagonist of dopamine D1-like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals?" Neuropharmacology 42(2): 237-45.
SKF 83959 that has a unique antiparkinson profile in animal models of Parkinson's disease is an in vitro dopamine D1 antagonist of receptors coupled to adenylyl cyclase. We hypothesized that SKF 83959, among others, interacts with dopamine D1 receptors coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. Effects of intra-accumbal injections of SKF 83959 on locomotor activity were compared to effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonist SCH 39166. Similarly to SCH 39166, SKF 83959 did not affect locomotor activity, but counteracted SKF 81297-induced locomotor activity. Effects of unilateral intra-prefrontal injections of SKF 83959 on rotational behaviour were compared to the effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonists SCH 23390 and SCH 39166 in rats selected on basis of their high locomotor response to novelty and pretreated with a subcutaneous injection of 0.75 mg/kg dexamphetamine. Like SCH 39166 and SCH 23390, SKF 83959 induced a bias for contralateral rotating and blocked the SKF 81297-induced bias for ipsilateral rotating. In conclusion, SKF 83959 is an in vivo antagonist of dopamine D1 receptors that are coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. The role of these receptors in the antiparkinson profile of SKF 83959 is discussed.

Cools, R., E. Stefanova, et al. (2002). "Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET." Brain 125(Pt 3): 584-94.
This study examined the effects of L-dopa medication in patients with Parkinson's disease on cortical and subcortical blood flow changes during two tasks known to involve frontostriatal circuitry. Eleven patients with Parkinson's disease were scanned on two occasions, one ON L-dopa medication and one OFF L-dopa medication, during performance of the Tower of London planning task and a related test that emphasized aspects of spatial working memory. L-dopa-induced decreases were observed in the right dorsolateral prefrontal cortex during performance of both the planning and the spatial working memory tasks compared with the visuomotor control task. Conversely, L-dopa-induced blood flow increases were observed in the right occipital lobe during the memory task relative to the control task. Data from age-matched healthy volunteers demonstrated that L-dopa effectively normalized blood flow in these regions in the patient group. Moreover, a significant correlation was found between L-dopa-induced, planning related blood flow decreases in the right dorsolateral prefrontal cortex and L-dopa-induced changes in performance on the planning task. These data suggest that L-dopa ameliorates high-level cognitive deficits in Parkinson's disease by inducing relative blood flow changes in the right dorsolateral prefrontal cortex.

Cunningham, L. A. and C. Su (2002). "Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease." Exp Neurol 174(2): 230-42.
Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease. A replication-defective retrovirus was constructed, which contained the rat GDNF sequence and a sequence encoding a beta-galactosidase (beta-gal)/neomycin phosphotransferase fusion protein, linked via an internal ribosomal entry site. Murine astrocytes transduced with this vector secreted GDNF into the culture media at the rate of 115 +/- 34 pg/24 h/10(5) cells and expressed cytoplasmic beta-gal, whereas control nontransduced astrocytes were negative for GDNF production and cytoplasmic beta-gal expression. Mice that received implants of GDNF-producing astrocytes into the striatum or nigra displayed elevated levels of GDNF compared to mice that received control nontransduced astrocytes. In addition, tissue content of GDNF was increased bilaterally and in brain regions both proximal and distal to the graft, even though astrocyte migration away from the graft site did not occur. Importantly, GDNF-producing astrocytes provided marked neuroprotection of nigral dopaminergic perikarya, and partial protection of striatal dopaminergic fibers, when implanted into the midbrain 6 days prior to a retrograde 6-OHDA lesion, as assessed by tyrosine hydroxylase immunohistochemistry. Similarly, GDNF-producing astrocytes prevented the acquisition of amphetamine-induced rotational behavior in 6-OHDA-treated mice and completely prevented dopamine depletion within the substantia nigra, as assessed by high-performance liquid chromatography. These results indicate that continuous exposure to low levels of GDNF provided by transgenic astrocytes provides marked neuroprotection of nigral dopaminergic neurons. (c)2002 Elsevier Science (USA).

Cyr, M., F. Calon, et al. (2002). "Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease." J Psychiatry Neurosci 27(1): 12-27.
Evidence suggests the estrogens may play a role in various mental and neurodegenerative diseases. We review the evidence implicating estradiol in schizophrenia and Parkinson's disease. Epidemiologic and clinical studies on the effects of estrogens in schizophrenia are surveyed, and animal studies and in vitro models of the modulatory effects of estrogens on neurotransmitters associated with schizophrenia (i.e., dopamine, serotonin, glutamate) are reviewed. Epidemiologic and clinical data suggesting a role for estrogens in Parkinson's disease and in vivo and in vitro models demonstrating neuroprotective effects of estrogens are then examined. Despite the numerous animal studies on the effects of estrogens in the brain, clinical data are sparse and often contradictory. Compounds with more specific and potent estrogenic activity in the brain are required to further research efforts in this area. Possible candidates are the selective estrogen receptor modulators (SERMs), whose agonist or antagonist properties depend on the target tissue. The effects of various SERMs in the brain are reviewed, and our novel findings on the effects of SERMs on 5-HT2A receptors in the rat cortex and nucleus accumbens are presented. We suggest that drugs with estrogenic activity in the brain may have therapeutic potential, either by modulating brain neurotransmission or through neuroprotective activity.

Danisi, F. (2002). "Parkinson's disease. Therapeutic strategies to improve patient function and quality of life." Geriatrics 57(3): 46-50; quiz 52.
Idiopathic Parkinson's disease (PD) is an age-related neuro-degenerative disorder characterized by slowness, stiffness, resting tremor, gait impairment, and postural instability. Levodopa is the most potent pharmacologic agent for symptom management and is associated with an increase in quality of life and longevity for patients with PD, but chronic use causes motor complications. The availability of several newer types of agents--dopamine agonists, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors--gives physicians increased flexibility with regard to first-line therapy, adjunct therapy, and managing or reducing the frequency of motor complications and other side effects associated with chronic levodopa therapy.

Deleu, D., M. G. Northway, et al. (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease." Clin Pharmacokinet 41(4): 261-309.
Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.

Dietrich, M., M. H. Hofmann, et al. (2002). "Effects of dopaminergic drugs and telencephalic ablation on eye movements in the goldfish, Carassius auratus." Brain Res Bull 57(3-4): 393-5.
The effect of the dopamine agonist apomorphine and the antagonist haloperidol on eye movements was tested in normal and telencephalon ablated goldfish. Reflex eye movements evoked by a rotating striped cylinder were not affected, which suggests that basic sensory and motor functions were not influenced by neither dopaminergic drugs nor the telencephalon. However, profound changes were observed in spontaneous eye movements. Particularly, the effect of apomorphine was similar to changes in eye movements observed in mammals after suppression of dopaminergic functions either by means of drugs or in patients suffering from Parkinson's disease or schizophrenia.

Duan, W., B. Ladenheim, et al. (2002). "Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease." J Neurochem 80(1): 101-10.
Although the cause of Parkinson's disease (PD) is unknown, data suggest roles for environmental factors that may sensitize dopaminergic neurons to age-related dysfunction and death. Based upon epidemiological data suggesting roles for dietary factors in PD and other age-related neurodegenerative disorders, we tested the hypothesis that dietary folate can modify vulnerability of dopaminergic neurons to dysfunction and death in a mouse model of PD. We report that dietary folate deficiency sensitizes mice to MPTP-induced PD-like pathology and motor dysfunction. Mice on a folate-deficient diet exhibit elevated levels of plasma homocysteine. When infused directly into either the substantia nigra or striatum, homocysteine exacerbates MPTP-induced dopamine depletion, neuronal degeneration and motor dysfunction. Homocysteine exacerbates oxidative stress, mitochondrial dysfunction and apoptosis in human dopaminergic cells exposed to the pesticide rotenone or the pro-oxidant Fe(2+). The adverse effects of homocysteine on dopaminergic cells is ameliorated by administration of the antioxidant uric acid and by an inhibitor of poly (ADP-ribose) polymerase. The ability of folate deficiency and elevated homocysteine levels to sensitize dopaminergic neurons to environmental toxins suggests a mechanism whereby dietary folate may influence risk for PD.

Ebadi, M., S. Sharma, et al. (2002). "Neuroprotective actions of selegiline." J Neurosci Res 67(3): 285-289.
Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B. Copyright 2002 Wiley-Liss, Inc.

Ebadi, M., S. Sharma, et al. (2002). "Neuroprotective actions of selegiline." J Neurosci Res 67(3): 285-9.
Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B.

Elble, R. J. (2002). "Tremor and dopamine agonists." Neurology 58(4 Suppl 1): S57-62.
Article abstract-Although all dopaminergic drugs are effective in reducing tremor, no single drug has been shown to be clearly superior in the treatment of tremor. Levodopa produces a mean improvement of 30 to 50% in the Unified Parkinson's Disease Rating Scale (UPDRS) subtest for rest tremor. Comparable improvement is achieved with the dopamine agonists. Dopamine agonists are particularly well suited for patients with newly diagnosed tremor-predominant disease and no cognitive impairment, but they are also useful in advanced patients with tremor that is refractory to levodopa and anticholinergics. The response of tremor to pharmacotherapy is variable, and clinicians must be prepared to try all of the available drugs before concluding that surgery is the only alternative.

Feger, J., M. Pessigliore, et al. (2002). "[Experimental models of Parkinson's disease]." Ann Pharm Fr 60(1): 3-21.
Parkinson's disease is a neurodegenerative condition who is related to a large loss of nigral dopaminergic neurons leading to a depletion of dopamine in the striatum. Experimental research is required in order to increase our knowledge on the cellular mechanism and functional consequences of this degenerative process. These models allow investigations of new therapeutics in order to improve the treatment of patients or to test new drugs able to protect any remaining dopaminergic neurons. It is relatively easy to obtain animal models of this disease since the target structure and the neuronal population are clearly defined. Two neurotoxic compounds are available for inducing animal models of Parkinson's disease, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A new one, rotenone, requires further investigations. Each of the neurotoxic compounds requires a specific protocol which can be used either with rodents or non-human primates. Progressive lesioning, using MPTP on green african monkeys (Cercopithecus aethiops sabaeus) provides the most reliable model of the idiopathic disease.

Fernandez Noda, E. I., H. Rivera Luna, et al. (2002). "New concept regarding chest pain due to hypoxia of the internal mammary arteries in more than 1,600 operated patients with cerebral thoracic neurovascular syndrome (CTNVS)." Panminerva Med 44(1): 47-59.
In this article we describe the role of compression of the vertebral, subclavian, internal mammary, internal carotid arteries, brachial plexus and coiling and kinking of the vertebral and basilar arteries, the faulty irrigation of blood supply and oxygen of the cerebellum and basal ganglia and other areas of the brain followed by metabolic processes. Among the effects are: a decrease in the secretion of dopamine at the level of the putamen, which produces the symptoms of symptomatic Parkinson's disease, chorea due to chronic transitory faulty blood supply and oxygen to the caudate nucleus, ballism by hypoxia at the level of sub-thalamic and thalamus nuclei and athetosis in the lenticular nucleus. This compression is caused by hypertrophy of the anterior scalenus muscles and the cervical ribs at the level of the vertebrae C6-C7; by the sternocleidomastoid at the level of the cervical atlas, by the pectoralis minor muscles and coiling and kinking of the vertebral, basilar and the internal carotid arteries. The decreased blood supply to the cerebellum and basal ganglia is the cause of the cerebral thoracic neuro vascular syndrome (CTNVS) and its neurological complications, among which are ipsilateral paralysis, symptomatic Parkinson's disease, functional Alzheimer's disease multiple sclerosis and others. We are presently engaged in genetic studies to widen our understanding of these illness.

Frackiewicz, E. J., S. S. Jhee, et al. (2002). "Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa." Ann Pharmacother 36(2): 225-30.
OBJECTIVE: To investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the dopamine transporter antagonist brasofensine (BMS-204756) in patients with Parkinson's disease receiving levodopa/carbidopa treatment. METHODS: A 4-period crossover study was performed in 8 men (mean age 66 y) with moderate Parkinson's disease (Hoehn-Yahr stage II-IV). A dose escalation study was used in which each patient was given a single oral dose of brasofensine 0.5, 1, 2, or 4 mg, which was coadministered with the patient's usual dose of levodopa/carbidopa. RESULTS: The maximum concentration (Cmax) values of brasofensine observed in plasma after oral administration were 0.35, 0.82, 2.14, and 3.27 ng/mL for the 0.5-, 1-, 2-, and 4-mg doses, respectively; these concentrations occurred 4 hours (time to Cmax) after administration in all cases. Exposure to brasofensine (based on AUC0-infinity) increased at a rate greater than proportional to dose. Based on the motor performance subscale of the Unified Parkinson's Disease Rating Scale, no change in patient disability was observed at any dose level. CONCLUSIONS: Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.

Fredduzzi, S., R. Moratalla, et al. (2002). "Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors." J Neurosci 22(3): 1054-62.
To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated l-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of l-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily l-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated l-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to l-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated l-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic l-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.

Freed, C. R. (2002). "Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson's disease?" Proc Natl Acad Sci U S A 99(4): 1755-7.

Frey, K. A. (2002). "Can SPET imaging of dopamine uptake sites replace PET imaging in Parkinson's disease?" Eur J Nucl Med 29(5): 715-7.

Frim, D. M. and H. N. Le (2002). "Gene therapy for Parkinson's disease." Expert Opin Biol Ther 2(2): 151-61.
Significant progress has been made in the field of gene therapy for Parkinson's disease (PD). Successful vehicles for gene transfer into the central nervous system have been developed and clinical efficacy and safety have both been shown in various animal models of PD. Further optimisation of dosing, timing and location of gene therapy delivery as well as the ability to regulate and prolong gene expression will be important for the commencement of human trials. Current gene therapy models for PD have focused on two treatment strategies. One is the replacement of biosynthetic enzymes for dopamine synthesis and the second strategy is the addition of neurotrophic factors for protection and restoration of dopaminergic neurones. Concepts of neuroprotection and restoration of the nigrostriatal pathway will become important themes for future genetic treatment strategies for PD and may include, in addition to neurotrophic factors, genes to prevent apoptosis or detoxify free radical species. This review will highlight the recent literature on gene therapy for PD and summarise general approaches to gene therapy.

Fukushima, T., A. Kaetsu, et al. (2002). "Possible role of 1-methylnicotinamide in the pathogenesis of Parkinson's disease." Exp Toxicol Pathol 53(6): 469-73.
This study tested the hypothesis, that nicotinamide N-methyltransferase (NAMT) activity in the brain could convert nicotinamide to 1-methylnicotinamide (MNA) and by that means damage the nigro-neostriatal dopaminergic neurons. The NAMT activities of rat brain and liver were assayed with gas chromatographic-mass spectrometric analysis in a selected ion monitoring system. They amounted to 0.30 nmol/mg x h and 0.51 nmol/mg x h, respectively. The MNA injection in rat substantia nigra pars compacta significantly decreased dopamine content in the striatum. NADH oxidation and lipid peroxidation by MNA via rat brain submitochondrial particles (SMP) under the condition of pH ranging from pH 6.0 to 10.0 were verified. The pH optimum for the NADH oxidation was 9.0. The pH optimum for the peroxidation of the lipid composing SMP by MNA was also 9.0. The lipid peroxidation in this assay was suppressed by superoxide dismutase. The superoxide anion formed by MNA via mitochondria might be involved in the etiology of Parkinson's disease.

Gao, H. M., J. S. Hong, et al. (2002). "Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons." J Neurosci 22(3): 782-90.
Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in rotenone-induced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuron-enriched cultures after treatment for 8 d with up to 20 nm rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nm rotenone or 8 d after treatment with 1 nm rotenone. The greatly enhanced neurodegenerative ability of rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to rotenone. Mechanistically, rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease.

Garcia Ruiz, P. and E. Meseguer (2002). "[Short history of L-Dopa]." Neurologia 17(4): 214-217.
The introduction of L-Dopa has been a landmark in Neuroscience. Before the use of L-Dopa, Parkinson's disease (PD) was considered a disabling disease with no effective treatment. The development of L-Dopa followed a rationale approach: first, the discovery of dopamine deficiency in the striatum of patients with PD; and then the use of precursor of dopamine. Overall, the whole process took less than 12 years; this is a remarkable short time taking into account that the development of a similar crucial drug such as insulin took 50 years. In addition, the success of L-Dopa stimulated the neurochemistry research for all neurodegenerative diseases.

Gayle, D. A., Z. Ling, et al. (2002). "Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide." Brain Res Dev Brain Res 133(1): 27-35.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Although the exact mechanisms responsible for this cell loss are unclear, emerging evidence suggests the involvement of inflammatory events. In the present study, we characterized the effects of the proinflammatory bacteriotoxin lipopolysaccharide (LPS) on the number of tyrosine hydroxylase immunoreactive (THir) cells (used as an index for DA neurons) in primary mesencephalic cultures. LPS (10-80 microg/ml) selectively decreased THir cells and increased culture media levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as well as nitrite (an index of nitric oxide (NO) production). Cultures exposed to both LPS and neutralizing antibodies to IL-1beta or TNF-alpha showed an attenuation of the LPS-induced THir cell loss by at least 50% in both cases. Inhibition of the inducible form of nitric oxide synthase (iNOS) by L-NIL did not affect LPS toxicity, but increased the LPS-induced levels of both TNF-alpha and IL-1beta. These findings suggest that neuroinflammatory stimuli which lead to elevations in cytokines may induce DA neuron cell loss in a NO-independent manner and contribute to PD pathogenesis.

Gerhardt, G. A., W. A. Cass, et al. (2002). "Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys." J Neurochem 80(1): 168-77.
For these studies, young (8-9 years), middle-aged (14-17 years) and aged (23-28 years) rhesus monkeys were used as a model of normal aging in humans to investigate changes in dopamine (DA)-containing neurons in senescence. Aged monkeys exhibited significant age-related motoric declines as compared to the young animals. In vivo microdialysis studies showed that basal levels of the DA metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were diminished by 44% and 79%, respectively, in the substantia nigra (SN) of aged monkeys. In addition, d-amphetamine-evoked overflow of DA in the SN was diminished by 30% in the middle-aged animals and 67% in the aged monkeys. Post-mortem measures of DA and DA metabolites showed significant decreases in DA (20%), DOPAC (47%) and HVA (22%) levels in the putamen and a 25% decline in HVA tissue levels in the SN of the aged monkeys as compared to the young animals. Unbiased stereological cell counting of tyrosine hydroxylase (TH)-immunoreactive neurons in the SN showed a small (15-20%) but significant age-related decline in TH-positive neurons. In addition, there was a small (15-20%) but significant decline in TH-positive fiber density and TH-positive cell size. In comparison to the massive loss of DA neurons responsible for the movement dysfunctions seen in Parkinson's disease, pronounced functional changes in DA release in the SN and putamen may significantly contribute to the motoric dysfunctions characterizing normal aging in rhesus monkeys.

Gouhier, C., S. Chalon, et al. (2002). "Protection of dopaminergic nigrostriatal afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease." Synapse 44(3): 124-31.
The use of glial cell line-derived neurotrophic factor (GDNF) appears to be a promising strategy to promote survival and function of the nigrostriatal dopaminergic pathway damaged in Parkinson's disease (PD). However, effective intracerebral administration is required for optimal therapeutic benefit and tools to evaluate such therapies must be developed. A rodent model of PD was therefore developed using striatal injection of 6-hydroxydopamine (6-OHDA) with simultaneous implantation of GDNF-delivering microspheres. The effects of GDNF released from microspheres were assessed by classical methods such as amphetamine-induced rotating behavior and tyrosine hydroxylase (TH) immunoreactivity, as well as by quantitative autoradiography using PE2I, a dopamine transporter (DAT) radiotracer, which is also suitable for SPET imaging in humans. 6-OHDA-lesioned animals that received microspheres without GDNF were used as controls. During the first 3 weeks after simultaneous lesion and implantation, the amphetamine-induced rotating behavior of GDNF-treated rats was improved compared to controls and an increase in TH expression (+26%) was measured in the striatum 6 weeks after lesion. In accordance with these results, an increase in striatal PE2I-labeled DAT density was obtained (+17%) after 3 and 6 weeks of treatment. In conclusion, this study demonstrates the neuroprotective action of GDNF delivered by microspheres and suggests that PE2I may be an appropriate radiotracer for use in SPET scintigraphy to follow up treatment of PD in humans.

Greenwood, T. A., M. Alexander, et al. (2002). "Segmental linkage disequilibrium within the dopamine transporter gene." Mol Psychiatry 7(2): 165-73.
The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3' repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5' (distal promoter through intron 6) and 3' (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Grieb, P. and R. Rejdak (2002). "Pharmacodynamics of citicoline relevant to the treatment of glaucoma." J Neurosci Res 67(2): 143-8.
Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated drug used in pharmacotherapy of brain insufficiency and some other neurological disorders, such as stroke, brain trauma, and Parkinson's disease. A few reports indicate that citicoline treatment may also be beneficial in glaucoma. Currently glaucoma is considered a neurodegenerative disease in which retinal ganglion cells (RGC) slowly die, likely in the apoptotic mechanism. Endogenous CDP-choline is a natural precursor of cellular synthesis of phospholipids, mainly phosphatydylcholine (PtdCho). Enhancement of PtdCho synthesis may counteract neuronal apoptosis and provide neuroprotection. Citicoline, when administered, undergoes a quick transformation to cytidine and choline, which are believed to enter brain cells separately and provide neuroprotection by enhancing PtdCho synthesis; similar effect may be expected to occur in glaucomatous RGC. Furthermore, citicoline stimulates some brain neurotransmitter systems, including the dopaminergic system, and dopamine is known as a major neurotransmitter in retina and postretinal visual pathways. In a double-blind, placebo-controlled study, treatment of glaucoma resulted in functional improvement in the visual system noted with electrophysiological methods. Development of citicoline as a treatment for glaucoma is indicated.

Gunal, D. I., K. Nurichalichi, et al. (2002). "The clinical profile of nonmotor fluctuations in Parkinson's disease patients." Can J Neurol Sci 29(1): 61-4.
OBJECTIVE: Recently described nonmotor fluctuations may cause disability in Parkinson's disease patients. These fluctuations are generally grouped as sensory, autonomic and psychiatric. The clinical spectrum and frequency of these fluctuating symptoms are not well-described. METHODS: We studied the relationship of nonmotor fluctuations with motor symptoms and determined the influence of age at disease onset, duration of disease, dosage and duration of levodopa treatment in the appearance of nonmotor fluctuations. RESULTS: Statistical analysis showed a relationship of disease-related parameters with sensory and autonomic fluctuations but psychiatric fluctuations were only found to be associated with the duration of levodopa usage. The nonmotor fluctuations included in the study were observed during "on" periods as well as "off' periods. CONCLUSION: Nonmotor fluctuations had variable presentations. Moreover, their co-appearance with different types of motor fluctuations may be linked to the effect of other neurotransmitter systems acting synchronously with dopamine. Risk factors for sensory and autonomic fluctuations in patients with Parkinson's disease were early age of disease onset, longer duration and higher dose of levodopa use. Psychiatric fluctuations were only associated with higher doses of levodopa.

Hartmann, A., A. Mouatt-Prigent, et al. (2002). "FADD: A link between TNF family receptors and caspases in Parkinson's disease." Neurology 58(2): 308-10.
Fas-associating protein with a death domain (FADD) is a proximal adaptor protein of the tumor necrosis factor (TNF) receptor family death pathway. This human postmortem study showed a significant decrease in the percentage of FADD-immunoreactive dopaminergic (DA) neurons in the substantia nigra pars compacta of patients with PD compared with controls (-24.8%). This decrease correlated with the known selective vulnerability of nigral DA neurons in PD, suggesting that this pathway contributes to the susceptibility of DA neurons in PD to TNF-mediated apoptosis.

Helfand, S. L. (2002). "Neurobiology. Chaperones take flight." Science 295(5556): 809-10.

Hemsley, K. M., E. J. Farrall, et al. (2002). "Dopamine receptors in the subthalamic nucleus are involved in the regulation of muscle tone in the rat." Neurosci Lett 317(3): 123-6.
The effects of injecting an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) bilaterally into the subthalamic nucleus (STN) on changes in muscle tone and behaviour were investigated. Increased muscle tone (i.e. rigidity) was assessed quantitatively as increases in tonic electromyographic (EMG) activity in the hindlimb muscles of conscious, unrestrained rats. Significant, sustained increases in EMG activity were observed for 3-5 h post-injection in the tibialis and gastrocnemius muscles following injection of EEDQ into the STN. This effect was associated with 73% dopamine D1 and 66% dopamine D2 receptor occupancy in the STN, while dopamine receptors in surrounding regions were minimally occupied. These results provide new evidence that dopamine receptors located in the STN play an important role in the regulation of normal muscle tone.

Hillion, J. A., M. Canals, et al. (2002). "Coaggregation, cointernalization and codesensitization of adenosine A2A receptors and dopamine D2 receptors." J Biol Chem.
Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D2R and in cultured striatal cells. A2AR/D2R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D2R-transfected SH-SY5Y cells and from mouse fibroblast Ltk- cells stably transfected with human D2R (long-form) and transiently cotransfected with the A2AR double tagged with haemagglutinin. Long-term exposure to A2AR and D2R agonists in D2R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A2AR and D2R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D2R are involved.

Hironishi, M., H. Miwa, et al. (2002). "[Benefit of L-DOPA-without-DCI (decarboxylase inhibitor) therapy on wearing-off phenomenon in advanced stages of Parkinson's disease patients]." No To Shinkei 54(2): 127-32.
Motor fluctuation is the most annoying complication experienced by patients in the advanced stages of Parkinson's disease. A Combination therapy of a dopamine receptor agonist and levodopa/DCI(DOPA-decarboxylase inhibitor) is commonly used to control the complication. Although administration of levodopa/DCI is useful in minimizing peripheral side effects of levodopa, it increases the incidence of motor complications due to the marked fluctuation of plasma levodopa level. The use of levodopa without DCI might be an option for controlling motor fluctuation, because the extent of plasma levodopa level fluctuation is smaller when levodopa is administered without DCI than with DCI. Six patients with Parkinson's disease who had troublesome motor complications under levodopa/DCI and DA agonist combination therapy were compared in terms of the extent of motor complications and their satisfaction after changing their therapy from levodopa/DCI to levodopa without DCI. The change from levodopa/DCI to levodopa(without DCI) was carried out all at once, and the levodopa/DCI to levodopa dose ratio was started at 1:4. The dose of levodopa(without DCI) was then increased gradually until motor complications improved or side effects were observed in patients. Except two patients who voluntarily quitted levodopa and restarted DOPA/DCI before the dose of levodopa fixed, all cases showed improvement of wearing-off phenomenon. No adverse event was observed. Levodopa-without-DCI-therapy was effective for controlling motor fluctuation in patients of Parkinson's disease in advanced stages.

Hobson, D. E., A. E. Lang, et al. (2002). "Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group." Jama 287(4): 455-63.
CONTEXT: Somnolence is a recognized adverse effect of dopamine agonists. Two new dopamine agonists, pramipexole and ropinirole, have been reported to cause sudden-onset sleep spells in patients with Parkinson disease (PD) while they were driving. The frequency of these spells and whether driving should be restricted has yet to be established. OBJECTIVE: To determine the frequency of and predictors for sudden-onset sleep and, particularly, episodes of falling asleep while driving among patients with PD. DESIGN, SETTING, AND PARTICIPANTS: Prospective survey conducted between January and April 2000 in 18 clinics directed by members of the Canadian Movement Disorders Group; 638 consecutive highly functional PD patients without dementia were enrolled, of whom 420 were currently drivers. MAIN OUTCOME MEASURES: Excessive daytime sleepiness and sudden-onset sleep as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score. The latter score, designed for this study, addressed falling asleep in unusual circumstances. The 2 scales were combined in 3 separate formats: dozing off, sudden unexpected sleep, and sudden blank spells. RESULTS: Excessive daytime sleepiness was present overall in 327 (51%) of the 638 patients and in 213 (51%) of the 420 drivers. Patients taking a variety of different dopamine agonists had no differences in Epworth sleepiness scores, in the composite score, or in the risk of falling asleep while driving. Sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving (after the diagnosis of PD); in 3 (0.7%), it occurred without warning. The 2 risk factors associated with falling asleep at the wheel were the Epworth Sleepiness Scale score (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.24) and the Inappropriate Sleep Composite Score (OR, 2.54; 95% CI, 1.76-3.66). A standard Epworth Sleepiness Scale score of 7 or higher predicted 75% of episodes of sleep behind the wheel at a specificity of 50% (exclusion of the question related to driving provided 70% sensitivity and 52% specificity), whereas a score of 1 on the Inappropriate Sleep Composite Score generated a sensitivity of 52% and specificity of 82%. CONCLUSIONS: Excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Sudden-onset sleep without warning is infrequent. The Epworth score has adequate sensitivity for predicting prior episodes of falling asleep while driving and its specificity can be increased by use of the Inappropriate Sleep Composite Score. It is unknown if routinely performing these assessments could be more effective in predicting future risk for these rare sleep attacks. Patients should be warned not to drive if they doze in unusual circumstances.

Hoogendam, A., J. Hofmeijer, et al. (2002). "[Severe parkinsonism due to metoclopramide in a patient with polypharmacy]." Ned Tijdschr Geneeskd 146(4): 175-7.
A 73-year-old woman, with tuberculosis of the large intestine, developed nausea as a side effect of the antituberculosis drugs. The nausea was treated with metoclopramide. Subsequently she developed severe medication-induced parkinsonism. As her symptoms initially mimicked a depressive disorder, drug-induced parkinsonism was only considered at a later stage. Due to drug-induced impaired function of the liver and kidney the patient had received a toxic dose of metoclopramide. Treatment with biperiden and withdrawal of the metoclopramide resulted in a reduction of the complaints within 3 months, after which the anti-tuberculosis medication could be reintroduced. Adjusting the dose of metoclopramide could possibly have prevented this severe side effect.

Hsieh, P. F., L. G. Chia, et al. (2002). "Behavior, neurochemistry and histology after intranigral lipopolysaccharide injection." Neuroreport 13(3): 277-80.
Inflammation and neuronal degeneration of the substantia nigra (SN) occur in Parkinson's disease (PD). We studied the effects of intranigral lipopolysaccharide (LPS) injection on adult Sprague-Dawley rats. Locomotor activity measurement, neurotransmitter determination and perfusion fixation for immunohistochemistry were done on the 7th day. Bilateral LPS injection increased locomotor activity 2- to 3-fold. In the SN, dopamine (DA) and serotonin (5-HT) decreased but the ratios dihydroxyphenylacetic acid (DOPAC)/DA, homovanillic acid (HVA)/DA and 5-hydroxyindole-acetic acid (5-HIAA)/5-HT increased. In the striatum, DA, DOPAC, HVA, 3-methoxytyramine and epinephrine decreased but HVA/DA and 5-HIAA/5HT ratios increased. Unilateral LPS decreased dopamineric neurons ipsilaterally but increased contralaterally. This study provides the first evidence of behavioral hyperactivity, epinephrine suppression and neuronal plasticity in the LPS model of PD.

Hubble, J. P. (2002). "Long-term studies of dopamine agonists." Neurology 58(4 Suppl 1): S42-50.
Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

Huotari, M., J. A. Gogos, et al. (2002). "Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice." Eur J Neurosci 15(2): 246-56.
Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.

Hwang, W. J., W. J. Yao, et al. (2002). "Downregulation of striatal dopamine D2 receptors in advanced Parkinson's disease contributes to the development of motor fluctuation." Eur Neurol 47(2): 113-7.
The purpose of this study was to evaluate the contribution of the postsynaptic mechanism to the development of motor fluctuation in advanced Parkinson's disease (PD). We used 123I-iodobenzamide single-photon emission computed tomography to measure the striatal dopamine D2 receptor densities in early levodopa-naive PD, chronic PD with stable levodopa response, and advanced PD with fluctuating levodopa response. The basal ganglia/frontal cortex ratios at both hemispheres were calculated and averaged. PD patients with fluctuating levodopa response showed a significant decrease in striatal dopamine D2 receptor densities compared to those with early (1.57+/- 0.20 vs. 1.77 +/- 0.12, p = 0.009) or chronic stable PD (1.57 +/- 0.20 vs. 1.77 +/- 0.10, p = 0.024). We conclude that the decreased D2 receptor densities in advanced PD reduced the 'safety factor' for synaptic transmission and contributed to the development of motor fluctuation.

Ikeda, K., M. Kurokawa, et al. (2002). "Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease." J Neurochem 80(2): 262-70.
Adenosine A2A receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A2A receptor-blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinson's disease. In the present study, a significant neuroprotective effect of A2A receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A2A antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A2A receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A2A receptor may provide a novel target for the long-term medication of Parkinson's disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.

Jenner, P. (2002). "Pharmacology of dopamine agonists in the treatment of Parkinson's disease." Neurology 58(4 Suppl 1): S1-8.
There is now increasing use of dopamine agonists as effective early monotherapy in the treatment of Parkinson's disease (PD). Dopamine agonists can induce an antiparkinsonian effect through actions on either D(1)-like or D(2)-like dopamine receptors, and the multiple receptor subtypes present in the brain may provide further opportunities to improve the treatment of PD. Functional interactions exist between D(1)- and D(2)-like receptors, and adaptive changes occur after denervation and repeated administration of a dopamine agonist. Long-acting dopamine agonists produce a lower incidence of dyskinesia than levodopa (L-dopa) when they are used as monotherapy in either PD or in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Continuous dopaminergic stimulation appears less likely to prime basal ganglia for involuntary movements compared with drugs, such as L-dopa, that produce pulsatile stimulation. However, once priming has occurred, dopamine agonists produce dyskinesia identical to that of L-dopa. Continuous administration of long-acting dopamine agonists may reverse the priming process initiated by L-dopa, markedly decreasing dyskinesia intensity with a minimal loss of antiparkinsonian activity, at least in MPTP-treated primates. Dopamine receptors in brain areas other than the striatum, such as the globus pallidus and subthalamic nucleus, and in the mesolimbic and mesocortical regions may also contribute to antiparkinsonian activity of dopamine agonists and their associated side effects. The future potential of dopamine agonists may lie in the selective stimulation of dopamine receptor subtypes in different brain areas and through the actions of partial dopamine agonists and drugs that normalize dopamine receptor function.

Jeyarasasingam, G., L. Tompkins, et al. (2002). "Stimulation of non-alpha7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture." Neuroscience 109(2): 275-85.
Previous work has shown that nicotine treatment protects against nigrostriatal degeneration in rodents, findings that may be of relevance to the decreased incidence of Parkinson's disease in cigarette smokers. In the present studies, we investigated the effect of nicotine against 1-methyl-4-phenylpyridinium-induced toxicity in dopaminergic ventral mesencephalic cultures to identify the nicotinic receptor population that may be involved. [3H]Epibatidine, a ligand that binds to receptors containing alpha2-alpha6 subunits, bound to at least two populations of sites that were up-regulated by nicotine in a time and dose dependent manner. We next examined the effect of nicotine on cultures treated with 1-methyl-4-phenylpyridinium, a neurotoxin that selectively damages nigrostriatal dopaminergic neurons. Pre-treatment with nicotine, at 10(-7)-10(-4) M, partially prevented the toxin-induced decline in dopaminergic cells. Pre-exposure to nicotine for 24 h resulted in optimal protection, suggesting that receptor up-regulation may contribute to the observed neuroprotective effect. Nicotine-mediated protection was blocked by pre-incubation with the nicotinic receptor antagonist d-tubocurarine (10(-4) M), but not the alpha7 receptor-selective antagonist alpha-bungarotoxin (10(-7) M).Our results show that nicotinic receptor activation partially protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture and that this appears to occur through an interaction at non-alpha7 containing receptors.

Jha, N., M. J. Kumar, et al. (2002). "Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: relevance for Parkinson's disease?" J Neurochem 80(4): 555-61.
Parkinson's disease (PD) is characterized by the presence of proteinaceous neuronal inclusions called Lewy bodies in susceptible dopaminergic midbrain neurons. Inhibition of the ubiquitin-proteasome protein degradation pathway may contribute to protein build-up and subsequent cell death. Ubiquitin is normally activated for transfer to substrate proteins by interaction with the E1 ubiquitin ligase enzyme via a thiol ester bond. Parkinson's disease is also characterized by decreases in midbrain levels of total glutathione which could impact on E1 enzyme activity via oxidation of the active site sulfhydryl. We have demonstrated that increasing reductions in total glutathione in dopaminergic PC12 cells results in corresponding decreases in ubiquitin-protein conjugate levels suggesting that ubiquitination of proteins is inhibited in a glutathione-dependent fashion. Decreased ubiquitinated protein levels appears to be due to inhibition of E1 activity as demonstrated by reductions in endogenous E1-ubiquitin conjugate levels as well as decreases in the production of de novo E1-ubiquitin conjugates when glutathione is depleted. This is a reversible process as E1 activity increases upon glutathione restoration. Our data suggests that decreases in cellular glutathione in dopaminergic cells results in decreased E1 activity and subsequent disruption of the ubiquitin pathway. This may have implications for neuronal degeneration in PD.

Johansson, S. and I. Stromberg (2002). "Guidance of dopaminergic neuritic growth by immature astrocytes in organotypic cultures of rat fetal ventral mesencephalon." J Comp Neurol 443(3): 237-49.
Astrocytes, with their many functions in producing and controlling the environment in the brain, are of great interest when it comes to studying regeneration after injury and neurodegenerative diseases such as in grafting in Parkinson's disease. This study was performed to investigate astrocytic guidance of growth derived from dopaminergic neurons using organotypic cultures of rat fetal ventral mesencephalon. Primary cultures were studied at different time points starting from 3 days up to 28 days. Cultures were treated with either interleukin-1 beta (IL-1 beta), which has stimulating effects on astrocytic proliferation, or the astrocytic inhibitor cytosine arabinoside (Ara-C). Tyrosine hydroxylase (TH)-immunohistochemistry was used to visualize dopaminergic neurons, and antibodies against glial fibrillary acidic protein (GFAP) and S100 beta were used to label astrocytes. The results revealed that a robust TH-positive nerve fiber production was seen already at 3 days in vitro. These neurites had disappeared by 5 days. This early nerve fiber outgrowth was not guided by direct interactions with glial cells. Later, at 7 days in vitro, a second wave of TH-positive neuritic outgrowth was clearly observed. GFAP-positive astrocytic processes guided these neurites. TH-positive neurites arborized overlying S100 beta-positive astrocytes in an area distal to the GFAP-positive astrocytic processes. Treatment with IL-1 beta resulted in an increased area of TH-positive nerve fiber network. In cultures treated with Ara-C, neither astrocytes nor outgrowth of dopaminergic neurites were observed. In conclusion, this study shows that astrocytes play a major role in long-term dopaminergic outgrowth, both in axonal elongation and branching of neurites. The long-term nerve fiber growth is preceded by an early transient outgrowth of dopamine neurites.

Junn, E. and M. M. Mouradian (2002). "Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine." Neurosci Lett 320(3): 146-50.
alpha-Synuclein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Two point mutations in alpha-synuclein (A53T and A30P) are identified in few families with dominantly inherited PD. Yet the mechanism by which this protein is involved in nigral cell death remains poorly understood. Mounting evidence suggests the importance of oxidative stress in the pathogenesis of PD. Here we investigated the effects of wild-type and two mutant forms of alpha-synuclein on intracellular reactive oxygen species (ROS) levels using clonal SH-SY5Y cells engineered to over-express these proteins. All three cell lines, and particularly mutant alpha-synuclein-expressing cells, had increased ROS levels relative to control LacZ-engineered cells. In addition, cell viability was significantly curtailed following the exposure of all three alpha-synuclein-engineered cells to dopamine, but more so with mutant alpha-synuclein. These results suggest that over-expression of alpha-synuclein, and especially its mutant forms, exaggerates the vulnerability of neurons to dopamine-induced cell death through excess intracellular ROS generation. Thus, these findings provide a link between mutations or over-expression of alpha-synuclein and apoptosis of dopaminergic neurons by lowering the threshold of these cells to oxidative damage.

Kannari, K., K. Kurahashi, et al. (2002). "[Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease]." No To Shinkei 54(2): 133-7.
A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson's disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson's disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson's disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone's potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.

Kashihara, K., Y. Manabe, et al. (2002). "Effects of short- and long-acting dopamine agonists on sensitized dopaminergic neurotransmission in rats with unilateral 6-OHDA lesions." Life Sci 70(9): 1095-100.
The effects of short and long-acting dopamine agonists on sensitized dopaminergic transmission in an animal model of Parkinson's disease were investigated. Rats with 6-hydroxydopamine (6-OHDA) lesions of the left nigrostriatal dopaminergic pathway were pre-exposed i.p. to 50 mg/kg methyl levodopa for 10 days. After a 7-day withdrawal period, these animals were treated with saline i.p., 0.05 mg/kg apomorphine s.c., or 0.5 mg/kg cabergoline i.p., once daily for 7 days. On the 8th day, rats in each treatment group received a challenge dose of 0.05 mg/kg apomorphine or saline s.c. The temporal changes in the number of rotations away from the 6-OHDA lesion side were evaluated after the challenge. The apomorphine challenge increased the number of rotations more markedly in the apomorphine pretreated rats than in the other pretreatment groups. In cabergoline pretreated rats, the number of rotations was significantly lower than that of saline-pretreated animals. Pretreatment with saline did not alter the apomorphine sensitivity of rotational behavior. These findings suggest that the repeated administration of long-acting dopamine agonists may reduce sensitized dopaminergic transmission in dopamine-depleted rats, whereas short-acting ones may further enhance sensitization of the transmission process.

Kawasaki, H., H. Suemori, et al. (2002). "Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity." Proc Natl Acad Sci U S A 99(3): 1580-5.
We previously identified a stromal cell-derived inducing activity (SDIA), which induces differentiation of neural cells, including midbrain tyrosine hydroxylase-positive (TH(+)) dopaminergic neurons, from mouse embryonic stem cells. We report here that SDIA induces efficient neural differentiation also in primate embryonic stem cells. Induced neurons contain TH(+) neurons at a frequency of 35% and produce a significant amount of dopamine. Interestingly, differentiation of TH(+) neurons from undifferentiated embryonic cells occurs much faster in vitro (10 days) than it does in the embryo (approximately 5 weeks). In addition, 8% of the colonies contain large patches of Pax6(+)-pigmented epithelium of the retina. The SDIA method provides an unlimited source of primate cells for the study of pathogenesis, drug development, and transplantation in degenerative diseases such as Parkinson's disease and retinitis pigmentosa.

Kim, J. R., K. S. Kwon, et al. (2002). "Oxidation of proteinaceous cysteine residues by dopamine-derived H2O2 in PC12 cells." Arch Biochem Biophys 397(2): 414-23.
Cellular metabolism of dopamine (DA) generates H2O2, which is further reduced to hydroxyl radicals in the presence of iron. Cellular damage inflicted by DA-derived hydroxyl radicals is thought to contribute to Parkinson's disease. We have previously developed procedures for detecting proteins that contain H2O2-sensitive cysteine (or selenocysteine) residues. Using these procedures, we identified ERP72 and ERP60, two members of the protein disulfide isomerase family, creatine kinase, glyceraldehyde-3-phosphate dehydrogenase, phospholipase C-gamma1, and thioredoxin reductase as the targets of DA-derived H2O2. Experiments with purified enzymes identified the essential Cys residues of creatine kinase and glyceraldehyde-3-phosphate dehydrogenase, that are specifically oxidized by H2O2. Although the identified proteins represent only a fraction of the targets of DA-derived H2O2, functional impairment of these proteins has previously been associated with cell death. The oxidation of proteins that contain reactive Cys residues by DA-derived H2O2 is therefore proposed both to be largely responsible for DA-induced apoptosis in neuronal cells and to play an important role in the pathogenesis of Parkinson's disease.

Kim, Y. J., M. Ichise, et al. (2002). "Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP." Mov Disord 17(2): 303-12.
It is often difficult to differentiate clinically between Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).The objective of this work was to investigate whether combined pre- and postsynaptic dopaminergic single photon emission computed tomography (SPECT) scanning can reliably demonstrate changes in the nigrostriatal dopaminergic system and help differentiate between normal controls, PD, MSA, and PSP patients. We performed SPECT evaluation of the dopamine transporter (DAT) and dopamine D2 receptors (D2). SPECT scans using [(123)I]beta-CIT (for DAT) and [(123)I]IBF (for D2) were performed in 18 patients with PD (12 dopa-naive and 6 on levodopa and/or dopamine agonists), 7 with MSA of the striatonigral degeneration type, 6 with PSP, and 29 normal controls. Antiparkinsonian drugs were withheld for at least 12 hours before the scans. DAT and D2 binding potentials (Rv = V(3)/V(2)) were measured for caudate, anterior, and posterior putamen on the sides ipsilateral and contralateral to the worst motor symptoms. DAT binding in the posterior putamen was markedly reduced in all patients. However, D2 binding in posterior putamen was significantly increased in dopa-untreated PD, being greater than the normal range in 4 of 12 (33%), and it was significantly reduced in MSA, being below the normal range in 5 of 7 (71%). None of the patients with PD showed reduced D2 binding below the normal range in posterior putamen. The degree of DAT binding could not discriminate between the patient groups. The ratio of posterior putamen to caudate percentage D2 Rv compared with the controls showed an opposite pattern between PD or PSP and MSA; the caudate was greater in 16 of 18 with PD and 6 of 6 with PSP, whereas caudate was less in 5 of 7 with MSA. These findings suggest that DAT SPECT may be useful in differentiating parkinsonism from controls and D2 SPECT in further differentiating MSA from Parkinson's disease and possibly PSP.

Kirik, D., B. Georgievska, et al. (2002). "Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer." Proc Natl Acad Sci U S A 99(7): 4708-13.
Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.

Kirik, D., C. Rosenblad, et al. (2002). "Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system." J Neurosci 22(7): 2780-91.
Recombinant adeno-associated viral vectors display efficient tropism for transduction of the dopamine neurons of the substantia nigra. Taking advantage of this unique property of recombinant adeno-associated viral vectors, we expressed wild-type and A53T mutated human alpha-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including alpha-synuclein-positive cytoplasmic inclusions and swollen, dystrophic neurites similar to those seen in brains from patients with Parkinson's disease, developed progressively over time. These pathological alterations occurred preferentially in the nigral dopamine neurons and were not observed in other nondopaminergic neurons transduced by the same vectors. The degenerative changes were accompanied by a loss of 30-80% of the nigral dopamine neurons, a 40-50% reduction of striatal dopamine, and tyrosine hydroxylase levels that was fully developed by 8 weeks. Significant motor impairment developed in those animals in which dopamine neuron cell loss exceeded a critical threshold of 50-60%. At 6 months, signs of cell body and axonal pathology had subsided, suggesting that the surviving neurons had recovered from the initial insult, despite the fact that alpha-synuclein expression was maintained at a high level. These results show that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant alpha-synuclein, pointing to a key role for alpha-synuclein in the pathogenesis of Parkinson's disease. Targeted overexpression of alpha-synuclein in the nigrostriatal system may provide a new animal model of Parkinson's disease that reproduces some of the cardinal pathological, neurochemical, and behavioral features of the human disease.

Kitamura, Y., J. Kakimura, et al. (2002). "Antiparkinsonian drugs and their neuroprotective effects." Biol Pharm Bull 25(3): 284-90.
In Parkinson's disease, while dopamine (DA) replacement therapy, such as with L-DOPA (levodopa), improves the symptoms, it does not inhibit the degeneration of DA neurons in the substantia nigra. Numerous studies have suggested that both endogenous and environmental neurotoxins and oxidative stress may participate in this disease, but the detailed mechanisms are still unclear. Recent genetic studies in familial Parkinson's disease and parkinsonism have shown several gene mutations. This new information regarding its pathogenesis offers novel prospects for effective strategies involving the neuroprotection of vulnerable DA neurons. This review summarizes current findings regarding the pathogenesis and antiparkinsonian drugs, and discusses their possibilities of targets to develop novel neuroprotective drugs.

Klein, R. L., M. A. King, et al. (2002). "Dopaminergic Cell Loss Induced by Human A30P alpha-Synuclein Gene Transfer to the Rat Substantia Nigra." Hum Gene Ther 13(5): 605-12.
Somatic cell gene transfer was used to express a mutant form of alpha-synuclein (alpha-syn) that is associated with Parkinson's disease (PD) in the rat substantia nigra (SN), a brain region that, in humans, degenerates during PD. DNA encoding the A30P mutant of human alpha-syn linked to familial PD was incorporated into an adeno-associated virus vector, which was injected into the adult rat midbrain. The cytomegalovirus/chicken beta-actin promoter was used to drive transgene expression. Over a 1-year time course, this treatment produced three significant features relevant to PD: (1) accumulation of alpha-syn in SN neuron perikarya, (2) Lewy-like dystrophic neurites in the SN and the striatum, and (3) a 53% loss of SN dopamine neurons. However, motor dysfunction was not found in either rotational or rotating rod testing. The lack of behavioral deficits, despite the significant cell loss, may reflect pathogenesis similar to that of PD, where greater than 50% losses occur before motor behavior is affected.

Klopman, G. and A. Sedykh (2002). "An MCASE approach to the search of a cure for Parkinson's Disease." BMC Pharmacol 2(1): 8.
BACKGROUND: Parkinson's disease is caused by a dopamine deficiency state in the fore brain area. Dopamine receptor agonists, MAO-B inhibitors, and N-Methyl-D-Aspartate (NMDA) receptor antagonists are known to have antiparkinson effect. Levodopa, a dopamine structural analog, is the best currently available medication for the treatment of Parkinsons disease. Unfortunately, it also induces side effects upon long administration time. Thus, multidrug therapy is often used, in which various adjuvants alleviate side effects of levodopa and enhance its antiparkinsonian action. RESULTS: Computer models have been created for three known antiparkinson mechanisms using the MCASE methodology. New drugs for Parkinsons disease can be designed on the basis of these models. We also speculate that the presence of biophores belonging to different groups can be beneficial and designed some potential drugs along this line. The proposed compounds bear pharmacophores of MAO-B inhibitors, dopamine agonists and NMDA antagonists, which could synergistically enhance their antiparkinson effect. CONCLUSIONS: The methodology could readily be expanded to other endpoints where drugs with multiple activity mechanisms would be desirable.

Koller, W. C. (2002). "Treatment of early Parkinson's disease." Neurology 58(4 Suppl 1): S79-86.
The early treatment of Parkinson's disease (PD) consists of nonpharmacologic treatment, consideration of neuroprotective therapy, and initial symptomatic treatment. Education for the patient and family, access to support groups, regular exercise, and good nutrition are essential to the overall management of PD. Disease-modifying therapies, such as agents that provide neurorescue or neuroprotection, will provide a major advance in the treatment of PD. Intervention at the genetic/environmental level or that affects the cascade of pathophysiologic events, protein aggregation, or apoptosis could result in neuroprotection. Many agents are now being investigated for neuroprotective potential. A major paradigm shift has recently occurred because of the recent basic and clinical data indicating that dopamine agonists, rather than levodopa, should be the initial symptomatic therapy in PD. However, levodopa may be started first in some patients because of patient age, cognitive status, or cost of drugs.

Korczyn, A. D. and M. Nussbaum (2002). "Emerging therapies in the pharmacological treatment of Parkinson's disease." Drugs 62(5): 775-86.
The pharmacological management of Parkinson's disease is a complex and dynamic task; there is no one 'right' strategy indicating which drugs should be used at a particular stage of the disease. There are now many different drugs belonging to several classes that may be effective, and there are still differences of opinion among leading clinicians about the best course of treatment. This review focuses on drug therapy for the motor impairment in Parkinson's disease. Current and future research directions are summarised by taking inventory of recent and innovative areas of development in the field, representing each category with at least one of its featured treatments. The main research efforts are being directed towards delaying the use of levodopa or finding therapies to be used as adjunct to it, in order to postpone motor complications and, in particular, dyskinesias. One of the recent trends is early employment of dopamine agonists. Additional efforts are being directed towards protecting and restoring dopamine neurons. Novel therapies acting on non-dopaminergic systems are also being researched.

Koutsilieri, E., S. Sopper, et al. (2002). "Involvement of dopamine in the progression of AIDS Dementia Complex." J Neural Transm 109(3): 399-410.
SUMMARY: HIV compromises immunological functions. Immune responses are regulated to a great extent by several molecules such as cytokines, neurotransmitters and hormones which interact with different immune effector cells and ultimately mediate the homeostatic responses to disease. Among these mediators, dopamine plays an important role. In this article we review AIDS Dementia Complex (ADC) and describe lines of evidence implying increased dopamine availability as a potent mediator of neurologic deficits in HIV infection and a factor exhibiting adverse effects on the progression of ADC.

Kulak, J. M., J. M. McIntosh, et al. (2002). "Loss of nicotinic receptors in monkey striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment is due to a decline in alpha-conotoxin MII sites." Mol Pharmacol 61(1): 230-8.
Nicotinic acetylcholine receptors (nAChRs) in the basal ganglia are a potential target for new therapeutics for Parkinson's disease. As an approach to detect expression of nAChRs in monkeys, we used 125I-epibatidine, an agonist at nAChRs containing alpha2 to alpha6 subunits. 125I-Epibatidine binding sites are expressed throughout the control monkey brain, including the basal ganglia. The alpha3/alpha6-selective antagonist alpha-conotoxin MII maximally inhibited 50% of binding in the caudate-putamen and had no effect on 125I-epibatidine binding in the frontal cortex or thalamus. In contrast, inhibition experiments with nicotine, cytisine, and 3-(2(S)-azetidinylmethoxy)pyridine-2HCl (A85380) showed a complete block of 125I-epibatidine binding in all regions investigated and did not discriminate between the alpha-conotoxin MII-sensitive and -insensitive populations in the striatum. To assess the effects of nigrostriatal damage, monkeys were rendered parkinsonian with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals with moderate striatal damage (dopamine transporter levels approximately 30% of control) had a 40 to 50% decrease in 125I-epibatidine binding. Inhibition studies showed that the decrease in epibatidine binding was due to loss of alpha-conotoxin MII-sensitive nAChRs. Monkeys with severe nigrostriatal damage (dopamine transporter levels < or = 5% of control) exhibited a 55 to 60% decrease in 125I-epibatidine binding, which seemed to be due to a complete loss of alpha-conotoxin MII nAChRs and a partial loss of other nAChR subtypes. These results show that nAChRs expressed in the primate striatum have similar affinities for nicotine, cytisine, and A85380, that alpha-conotoxin MII discriminates between nAChR populations in the caudate and putamen, and that alpha-conotoxin MII-sensitive nAChRs are selectively decreased after MPTP-induced nigrostriatal damage.

Kuriwaka, R., T. Mitsui, et al. (2002). "Loss of postural reflexes in long-term occupational solvent exposure." Eur Neurol 47(2): 85-7.
Inhalation of organic solvents has long been known to damage various nervous systems, including cerebellum, brainstem, and pyramidal tract. However, little is known about the damage of the dopaminergic system. We report two patients with occupational long-term solvent exposure who developed postural instability without other features of parkinsonism. The concentration of HVA in CSF was decreased and the retropulsion was dramatically improved after the administration of levodopa. These findings indicate that the nigrostriatal dopaminergic neurons were disturbed by chronic solvent exposure, resulting in the loss of postural reflexes.

Leret, M. L., J. A. San Millan, et al. (2002). "Deprenyl protects from MPTP-induced Parkinson-like syndrome and glutathione oxidation in rat striatum." Toxicology 170(3): 165-71.
An intrastriatal injection with 18.8 nmoles of the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced in rats a progressive parkinsonism characterized by a major loss of striatum dopamine (DA) levels and an increased turnover of this neurotransmitter 96 h after the administration. In addition, the intrastriatal administration of MPTP produced an alteration in various behavioral markers of motor activity. Loss of DA was accompanied by a significant decrease of reduced glutathione (GSH) and an increase in GSH oxidation in the striatum. When deprenyl (10 mg/kg) was i.p. administered 2 h before the intrastriatal injection of MPTP, DA, GSH, glutathione redox status and the indexes of motor activity were not altered. These results show that MPTP increases striatum oxidative stress leading to cellular and in vivo degenerative changes which are prevented by pretreatment with deprenyl.

Levites, Y., M. B. Youdim, et al. (2002). "Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures." Biochem Pharmacol 63(1): 21-9.
Antioxidant and anti-inflammatory therapy approaches have been in the focus of attention in the treatment of neurodegenerative Parkinson's and Alzheimer's diseases where oxidative stress has been implicated. Tea extracts have been previously reported to possess radical scavenger, iron chelating and anti-inflammatory properties in a variety of tissues. The purpose of this study was to investigate potential neuroprotective effects of tea extracts and possible signal pathway involved in a neuronal cell model of Parkinson's disease. We demonstrated highly potent antioxidant-radical scavenging activities of green tea (GT) and black tea (BT) extracts on brain mitochondrial membrane fraction, against iron (2.5 microM)-induced lipid peroxidation. Both extracts (0.6-3 microM total polyphenols) were shown to attenuate the neurotoxic action of 6-hydroxydopamine (6-OHDA)-induced neuronal death. 6-OHDA (350 and 50 microM) activated the iron dependent inflammatory redox sensitive nuclear factor-kappaB (NF-kappaB) in rat pheochromocytoma (PC12) and human neuroblastoma (NB) SH-SY5Y cells, respectively. Immunofluorescence and electromobility shift assays showed increased nuclear translocation and binding activity of NF-kappaB after exposure to 6-OHDA in NB SH-SY5Y cells, with a concomitant disappearance from the cytoplasm. Introduction of GT extract (0.6, 3 microM total polyphenols) before 6-OHDA inhibited both NF-kappaB nuclear translocation and binding activity induced by this toxin in NB SH-SY5Y cells. Neuroprotection was attributed to the potent antioxidant and iron chelating actions of the polyphenolic constituents of tea extracts, preventing nuclear translocation and activation of cell death promoting NF-kappaB. Brain penetrating property of polyphenols may make such compounds an important class of drugs for treatment of neurodegenerative diseases.

Ling, Z., D. A. Gayle, et al. (2002). "In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain." Mov Disord 17(1): 116-24.
We investigated whether in utero exposure to the Gram(-) bacteriotoxin lipopolysaccharide (LPS) induces dopamine (DA) neuron loss in rats. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) kills DA neurons and is elevated in the brains of patients with Parkinson's disease (PD). LPS is a potent inducer of TNF-alpha, and both are increased in the chorioamniotic environment of women who have bacterial vaginosis (BV) during pregnancy, suggesting that BV might interfere with the normal development of fetal DA neurons. Gravid female rats were injected intraperitoneally with either LPS or normal saline at embryonic day 10.5 and their pups were killed at postnatal day 21. The brains of the pups were assessed for DA and TNF-alpha levels and DA cell counts in the mesencephalon using tyrosine hydroxylase immunoreactive (THir) cells as a DA neuron marker. Prenatal LPS exposure significantly reduced striatal DA (29%) and increased DA activity (72%) as well as TNF-alpha (101%). Stereological cell counts in the mesencephalon were also significantly reduced (27%) by prenatal LPS exposure. Prenatal exposure to LPS, as might occur in humans with BV, produces a significant loss of THir cells in rats that is still present 33 days following a single injection of LPS. Since this cell loss is well past the normal phase of DA neuron apoptosis that occurs in early postnatal life, rats so exposed may have a permanent loss of DA neurons, suggesting that prenatal infections may represent risk factors for PD.

Ludin, H. P. (2002). "[In Process Citation]." Schweiz Rundsch Med Prax 91(10): 407-10.
Many patients suffering from Parkinson's disease complain about chronic fatigue and daytime somnolence. During the last few years attention has been drawn to "sleep attacks", which are supposed to be due mainly to dopamine agonists. Sleep disturbances during the night are quite frequent. It is important to search for the probable causes in each individual case in order to be able to install an efficacious treatment.

Lundblad, M., M. Andersson, et al. (2002). "Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease." Eur J Neurosci 15(1): 120-32.
In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.

Malapani, C., B. Deweer, et al. (2002). "Separating storage from retrieval dysfunction of temporal memory in Parkinson's disease." J Cogn Neurosci 14(2): 311-22.
Dysfunction of the basal ganglia and the brain nuclei interconnected with them leads to disturbances of movement and cognition exemplified in Parkinson's disease (PD) and Huntington's disease, including disordered timing of movements and impaired time estimation. Previous research has shown that whereas striatal damage in animals can result in the loss of temporal control over behavior, dopaminergic deregulation in the human striatum associated with PD distorts the memory for time. Here we show a dissociation between deficits in storage (writing to) and retrieval (reading from) temporal memory processes. Both are dysfunctional in PD and sensitive to treatment with dopaminergic agents, but produce dissimilar distortions. When time intervals are stored in memory while the subjects are dopamine depleted, the process is slowed, leading to overestimation of two different time intervals. Conversely, when retrieval occurs in a dopamine-depleted state, interference or coupling occurs between two remembered time intervals, producing overestimation of the shorter and underestimation of the longer one. Whether those two separable patterns of dysfunction in storing and retrieving temporal memories rely on distinct neural networks within the basal ganglia and/or their cortical targets remains to be answered by future research.

Marek, K., J. Seibyl, et al. (2002). "Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression." Jama 287(13): 1653-61.
CONTEXT: Pramipexole and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients. OBJECTIVE: To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2beta-carboxymethoxy-3beta(4-iodophenyl)tropane (beta-CIT) labeled with iodine 123. DESIGN: Substudy of a parallel-group, double-blind randomized clinical trial. SETTING AND PATIENTS: Eighty-two patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997. INTERVENTIONS: Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n = 40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified. MAIN OUTCOME MEASURES: The primary outcome variable was the percentage change from baseline in striatal [(123)I]beta-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [(123)I]beta-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications. RESULTS: Sequential SPECT imaging showed a decline in mean (SD) [(123)I]beta-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months-approximately 5.2% per year. The mean (SD) percentage loss in striatal [(123)I]beta-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P =.004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P =.009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P =.01). The percentage loss from baseline in striatal [(123)I]beta-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation (r = - 0.40; P =.001). CONCLUSIONS: Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [(123)I]beta-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.

Maruyama, W., T. Takahashi, et al. (2002). "The anti-parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells." J Neural Transm 109(4): 467-81.
SUMMARY: Clinical trials for treatment of Parkinson's disease suggest that (-)deprenyl (selegiline), an inhibitor of type B monoamine oxidase, may slow the disease progression. However, the mechanism underlying protection of nigral dopamine neurons by selegiline remains an enigma. Recently, rasagiline, (R)(+)-N-propargyl-1-aminoindan, was reported to be neuroprotective by in vivo and in vitro experiments, which is another selective irreversible inhibitor of type B monoamine oxidase and not metabolized into amphetamine-like derivatives as in the case of selegiline. In this paper, the mechanism of the neuroprotection was examined using human dopaminergic neuroblastoma SH-SY5Y cells against apoptosis induced by peroxynitrite generated from SIN-1. After treatment with SIN-1, the apoptotic DNA damage in the cells was quantified by a single cell gel electrophoresis (comet) assay and by staining with Hoechst 33342. Change in mitochondrial membrane potential, Deltapsim, was measured by use of a fluorescent indicator, JC-1. Rasagiline reduced apoptosis with much more potency than selegiline, and the protection required 20 min pre-incubation before SIN-1 treatment. The protection by rasagiline was proved to be due to stabilization of mitochondrial membrane potential against the collapse induced by SIN-1, whereas rasagiline did not scavenge peroxynitrite directly. The studies on structure-activity relationship showed that a propargylamine group and a hydrophobic group with an adequate intermediate space were required for the protection. These results suggest that rasagiline may protect declining neurons through its anti-apoptotic activity in neurodegenerative diseases.

Matsubara, E., M. Shoji, et al. (2002). "[The treatment of Parkinson's disease--adenosine A2A receptor antagonists]." Nippon Rinsho 60(1): 112-6.
The primary pathology of Parkinson's disease is the degeneration of dopaminergic neurons in the nigrostriatal pathway, resulting in a significant reduction in striatum dopamine concentration which is responsible for the altered motor functions. With time and disease progression, efficacy of dopaminergic therapy becomes unpromising. Since adenosine A2A receptor is selectively localized in striatum for controlling motor activity, it appeared to be an attractive target for a novel treatment in Parkinson's disease. Several lines of evidence indicated that KW-6002, highly selective antagonist of adenosine A2A receptor, showed anti-parkinsonian effect in vivo and in vitro without any problematic side effect which is observed in dopaminergic therapy. Further investigation will be necessary to make sure the effect in ongoing progressive nature of Parkinson's disease or the long treatment periods in Parkinson's disease.

Mattay, V. S., A. Tessitore, et al. (2002). "Dopaminergic modulation of cortical function in patients with Parkinson's disease." Ann Neurol 51(2): 156-64.
Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region.

Mendez, I., A. Dagher, et al. (2002). "Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases." J Neurosurg 96(3): 589-96.
The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson's Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

Metz, G. A. and I. Q. Whishaw (2002). "Drug-induced rotation intensity in unilateral dopamine-depleted rats is not correlated with end point or qualitative measures of forelimb or hindlimb motor performance." Neuroscience 111(2): 325-36.
The pharmacological induction of rotational (circling) behavior is widely used to assess the effects of lesions to the dopaminergic system and the success of treatment strategies in rat models of Parkinson's disease. While the number of rotations under apomorphine, L-DOPA and amphetamine is related to the extent of dopamine depletion after unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system, the relationship of the intensity of rotational behavior to the degree of impairment in motor behavior is unclear. The present study examined this question by correlating rotational behavior and motor abilities in a rat analogue for Parkinson's disease produced by unilateral nigrostriatal bundle lesion with 6-hydroxydopamine. Ipsiversive and contraversive rotation was measured in the rats following systemic administration of low and high doses of apomorphine, the dopamine precursor L-DOPA, and amphetamine. The motor assessment included end point and qualitative measures of fore- and hindlimbs assessed in a skilled reaching task and a skilled ladder rung walking task. The intensity of drug-induced rotation did not correlate with the measures of motor performance.We conclude that independence of rotational behavior and motor performance argues that both the assessment of 6-hydroxydopamine behavioral deficits and potential treatments for the functional deficits require comprehensive assessment, including both measures of rotation and motor behavior.

Midlov, P., A. Bondesson, et al. (2002). "Descriptive study and pharmacotherapeutic intervention in patients with epilepsy or Parkinson's disease at nursing homes in southern Sweden." Eur J Clin Pharmacol 57(12): 903-10.
OBJECTIVES: To describe the drug use in epilepsy and Parkinson's patients living in nursing homes and to evaluate the impact of multi-speciality team intervention on health-related quality of life, activities of daily living (ADL) and confusion state. METHODS: Nursing home residents with epilepsy or Parkinson's disease in the county of Skane in Sweden were identified. From 119 nursing homes, 262 patients were identified. After obtaining informed consent, 157 patients from 48 nursing homes were included. Of these patients 74 were diagnosed with epilepsy and 84 with Parkinson's disease (one patient had both diagnoses). The average age of the epilepsy patients was 79 years and of the Parkinson's patients 81 years. Pharmacists documented the patients' drug use and any drug-related problems after communication with nursing-home residents, their contact persons at the nursing home and the residents' physicians. A multi-speciality group consisting of pharmacists, a primary care physician, a neurologist, a neuro-psychiatrist and a clinical pharmacologist evaluated the patients' medication and, when appropriate, suggested changes. Lists of each resident's medications were collected together with information about drug-related problems. The use of drugs deemed inappropriate for geriatric nursing-home residents according to Beer's criteria was documented. Health-related quality of life was evaluated using a generic health-related quality of life instrument, SF-36. Confusion state was measured using the Behaviour Pathology in Alzheimer's Disease Rating Scale (Behave-AD), and ability to perform ADL was assessed using the Schwab and England capacity for daily living scale. All measurements were repeated after approximately 6 months. During that period, for the group randomised to active intervention, the physicians involved in the care of the patients had received the recommendations for changes in drug treatment from the multi-speciality group. RESULTS: Epilepsy patients at nursing homes used on average 8.0 drugs for continuous use whereas Parkinson's patients used 8.6 drugs. According to Beer's criteria about 40% of both patient groups used drugs that are classified as inappropriate to geriatric nursing-home patients. Dopamine receptor-blocking psychotropic drugs were used by 29% of the Parkinson's patients. Indication for a patient's total drug treatment was not documented for 50% of epilepsy and 40% of Parkinson's patients. There were no significant differences between the active and control groups in changes in SF-36, Behave-AD or ADL for epilepsy patients. For Parkinson's patients there was a significant decrease in ADL for the active group, whereas there were no differences in SF-36 or Behave-AD. CONCLUSION: Nursing-home residents with epilepsy or Parkinson's disease use many drugs and often drugs that are classified as inappropriate. A simple problem-oriented questionnaire may be helpful in identifying specific drug-related problems in geriatric patients with common neurological diseases. Methods on how to improve the pharmacotherapy of these patients still have to be developed.

Miyasaki, J. M., W. Martin, et al. (2002). "Practice parameter: Initiation of treatment for Parkinson's disease: An evidence-based review: Report of the Quality Standards Subcommittee of the American Academy of Neurology." Neurology 58(1): 11-7.
In 1993, the last AAN Practice Parameter on medical treatment of Parkinson's disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence).

Momose, Y., M. Murata, et al. (2002). "Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms." Ann Neurol 51(1): 133-6.
We studied 20 single nucleotide polymorphisms in 18 candidate genes for association with Parkinson's disease. We found that homozygosity for the V66M polymorphism of the brain-derived neurotrophic factor (BDNF) gene occurs more frequently in patients with Parkinson's disease than in unaffected controls (chi(2) = 5.46) and confirmed an association with the S18Y polymorphism of the UCH-L1 gene. Our results provide genetic evidence supporting a role for BDNF in the pathogenesis of Parkinson's disease.

Muller, T. (2002). "Drug treatment of non-motor symptoms in Parkinson's disease." Expert Opin Pharmacother 3(4): 381-8.
Non-motor symptoms may considerably reduce parkinsonian quality of life, particularly in advanced stages of the disease. Autonomic features, such as seborrhoea, hyperhidrosis, orthostatic hypotension, excessive salivation, bladder dysfunction and GI disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis and dementia, appear in the course of Parkinson's disease. Pharmacotherapy of these non-motor symptoms complicates long-term antiparkinsonian combination drug therapy due to possible drug interactions, side effects and changes in metabolism. Moreover, antiparkinsonian compounds themselves contribute to the onset of these non-motor symptoms to a considerable extent. This complicates differentiation between the disease process itself and drug-related effects, thus influencing therapeutic options, which are often limited because of comorbidity and polypharmacy. Therefore, standardised recommendations are questionable, since drug tolerability and response differ between patients. Nevertheless, this review tries to provide a survey of possible therapeutic options for the treatment of the symptoms of Parkinson's disease other the dopamine-sensitive motor features.

Muller, T., S. Benz, et al. (2002). "Tapping and peg insertion after levodopa intake in treated and de novo parkinsonian patients." Can J Neurol Sci 29(1): 73-7.
BACKGROUND: Investigators use instrumental tasks for objective assessment of parkinsonian motor disability and its drug response. To date, such studies on treated parkinsonian patients have not addressed acute and long-term effects of dopaminergic drugs. OBJECTIVES: To determine the impact of long-term dopaminergic therapy within a standardized levodopa challenge test design in combination with two repeatedly performed instrumental tasks, peg insertion and tapping, in previously treated and untreated parkinsonian patients. RESULTS: Tapping significantly deteriorated in previously untreated, but not in treated parkinsonian patients after levodopa intake. In contrast, motor symptoms and peg insertion significantly improved in both groups of parkinsonian patients. Results of both tests differed between parkinsonian patients and matched controls. CONCLUSION: Worsening of cognitively less demanding tapping may result from upregulated presynaptic inhibitory feedback regulation, sedative effects of levodopa or dopamine overflow in untreated parkinsonian patients, who are sensitive to these effects in contrast to treated parkinsonian patients. Tapping is a task with autonomic repetitive performance and programming of standardised movements with a low need for cognitive effort. This autonomic functioning of attentional control and selective processing is intact in Parkinson's disease. Peg insertion depends on more complex movements and thus hypothetically on dopamine-associated cognitive processes. Therefore, impairment of peg insertion responded to dopaminergic stimulation in both groups of parkinsonian patients. Future studies on the efficacy of antiparkinsonian drugs, using instrumental tasks for objective assessment, should consider long-term impact of antiparkinsonian drug therapy and associated cognitive efforts.

Mummery, C. L. (2002). "[In Process Citation]." Tijdschr Diergeneeskd 127(6): 189-91.
Human embryonic stem cells are of great importance, and Parkinson's disease is given as an example of a condition that could benefit from the development of stem cell-based transplantation therapies. The reason for this is fairly obvious: the disease is caused by the loss of only one cell type from the brain that has one major function, namely the production of dopamine. Replacement of these cells should in principle cure the disease. But what are stem cells and how far is scientific research from being able to offer stem cell-based therapy in the clinic to patients suffering from Parkinson's disease, and other chronic diseases? These questions are addressed here together with a critical evaluation of short and long-term clinical perspectives, and a discussion of possible alternatives such as adult stem cells.

Muramatsu, S., K. Fujimoto, et al. (2002). "Behavioral recovery in a primate model of Parkinson's disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes." Hum Gene Ther 13(3): 345-54.
One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associated virus (AAV) vectors, we previously demonstrated that expression of these three enzymes in the striatum resulted in long-term behavioral recovery in rat models of PD. We here extend the preclinical exploration to primate models of PD. Mixtures of three separate AAV vectors expressing TH, AADC, and GCH, respectively, were stereotaxically injected into the unilateral putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. Coexpression of the enzymes in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-TH/-AADC/-GCH-injected side. Behavioral recovery persisted during the observation period (four monkeys: 48 days, 65 days, 50 days, and >10 months, each). TH-immunoreactive (TH-IR), AADC-IR, and GCH-IR cells were present in a large region of the putamen. Microdialysis demonstrated that concentrations of DA in the AAV-TH/-AADC/-GCH-injected putamen were increased compared with the control side. Our results show that AAV vectors efficiently introduce DA-synthesizing enzyme genes into the striatum of primates with restoration of motor functions. This triple transduction method may offer a potential therapeutic strategy for PD.

Nakazato, T. and A. Akiyama (2002). "Behavioral activity and stereotypy in rats induced by L-DOPA metabolites: a possible role in the adverse effects of chronic L-DOPA treatment of Parkinson's disease." Brain Res 930(1-2): 134-42.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is a common and effective treatment for Parkinson's disease, but dyskinesia continues to be a serious adverse effect with chronic use. Evidence suggests that L-DOPA induces increases in dopamine, which then binds to supersensitive dopamine receptors, resulting in dyskinesia. We have shown previously that L-DOPA directly causes stereotypy in rats, suggesting that chronic L-DOPA-induced dyskinesia is also caused by L-DOPA itself. This raises the possibility that other L-DOPA metabolites have a role in dyskinesia. We examined the behavioral effects of five L-DOPA metabolites (3-methoxytyramine, 3-MT; 3,4-dihydroxyphenylalanine, DOPAC; dopamine; homovanillic acid, and 3-o-methyl-DOPA) in rats. A unilateral, intracerebroventricular injection of 3-MT (10-200 microg, 40 microl) over 30 min, dose-dependently increased behavioral activity and stereotypy. This effect was suppressed by the dopamine D1/5-receptor antagonist SCH 23390, but not by the dopamine D2/3/4-receptor antagonist sulpiride. Dopamine denervation resulted in behavioral supersensitivity to 3-MT. Neither dopamine nor DOPAC levels increased in the striatum after 3-MT administration, as measured using in vivo voltammetry. The behavioral changes paralleled a rise in 3-MT in the contralateral striatum. DOPAC also caused behavioral changes and stereotypy, but to a smaller degree than 3-MT. Dopamine-denervated rats did not exhibit a supersensitive response to DOPAC, however. Other L-DOPA metabolites did not cause behavioral effects. These data suggest that 3-MT directly induced dopamine-D1/5-receptor-mediated behavioral changes in rats, and that 3-MT may have a role in dyskinesia due to chronic L-DOPA treatment in Parkinson's disease patients.

Nass, R., D. H. Hall, et al. (2002). "Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans." Proc Natl Acad Sci U S A 99(5): 3264-9.
Parkinson's disease is a complex neurodegenerative disorder characterized by the death of brain dopamine neurons. In mammals, dopamine neuronal degeneration can be triggered through exposure to neurotoxins accumulated by the presynaptic dopamine transporter (DAT), including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium. We have established a system for the pharmacological and genetic evaluation of neurotoxin-induced dopamine neuronal death in Caenorhabditis elegans. Brief (1 h) exposure of green fluorescent protein-tagged, living worms to 6-OHDA causes selective degeneration of dopamine neurons. We demonstrate that agents that interfere with DAT function protect against 6-OHDA toxicity. 6-OHDA-triggered neural degeneration does not require the CED-3/CED-4 cell death pathway, but is abolished by the genetic disruption of the C. elegans DAT.

Neuhoff, H., A. Neu, et al. (2002). "I(h) channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain." J Neurosci 22(4): 1290-302.
Dopaminergic (DA) midbrain neurons in the substantia nigra (SN) and ventral tegmental area (VTA) are involved in various brain functions such as voluntary movement and reward and are targets in disorders such as Parkinson's disease and schizophrenia. To study the functional properties of identified DA neurons in mouse midbrain slices, we combined patch-clamp recordings with either neurobiotin cell-filling and triple labeling confocal immunohistochemistry, or single-cell RT-PCR. We discriminated four DA subpopulations based on anatomical and neurochemical differences: two calbindin D28-k (CB)-expressing DA populations in the substantia nigra (SN/CB+) or ventral tegmental area (VTA/CB+), and respectively, two calbindin D28-k negative DA populations (SN/CB-, VTA/CB-). VTA/CB+ DA neurons displayed significantly faster pacemaker frequencies with smaller afterhyperpolarizations compared with other DA neurons. In contrast, all four DA populations possessed significant differences in I(h) channel densities and I(h) channel-mediated functional properties like sag amplitudes and rebound delays in the following order: SN/CB- --> VTA/CB- --> SN/CB+ --> VTA/CB+. Single-cell RT-multiplex PCR experiments demonstrated that differential calbindin but not calretinin expression is associated with differential I(h) channel densities. Only in SN/CB- DA neurons, however, I(h) channels were actively involved in pacemaker frequency control. In conclusion, diversity within the DA system is not restricted to distinct axonal projections and differences in synaptic connectivity, but also involves differences in postsynaptic conductances between neurochemically and topographically distinct DA neurons.

Nguimfackmbodie, P. C. (2002). "[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?]." Encephale 28(2): 147-53.
The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.

Nie, G., C. Jin, et al. (2002). "Distinct effects of tea catechins on 6-hydroxydopamine-induced apoptosis in PC12 cells." Arch Biochem Biophys 397(1): 84-90.
Green tea polyphenols have aroused considerable attention in recent years for preventing oxidative stress related diseases including cancer, cardiovascular disease, and degenerative disease. Neurodegenerative diseases are cellular redox status dysfunction related diseases. The present study investigated the different effects of the five main components of green tea polyphenols on 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells, the in vitro model of Parkinson's disease (PD). When the cells were treated with five catechins respectively for 30 min before exposure to 6-OHDA, (-)-epigallocatechins gallate (EGCG) and (-)-epicatechin gallate (ECG) in 50-200 microM had obvious concentration-dependent protective effects on cell viability, while (-)-epicatechin (EC), (+)-catechin ((+)-C), and (-)-epigallocatechin (EGC) had almost no protective effects. The five catechins also showed the same pattern described above of the different effects against 6-OHDA-induced cell apoptotic characteristics as analyzed by cell viability, fluorescence microscopy, flow cytometry, and DNA fragment electrophoresis methods. The present results indicated that 200 microM EGCG or ECG led to significant inhibition against typical apoptotic characteristics of PC12 cells, while other catechins had little protective effect against 6-OHDA-induced cell death. Therefore, the classified protective effects of the five catechins were in the order ECG> or = EGCG>>EC> or = (+)-C>>EGC. The antiapoptotic activities appear to be structurally related to the 3-gallate group of green tea polyphenols. The present data indicate that EGCG and ECG might be potent neuroprotective agents for PD.

Nieves, A. V. and A. E. Lang (2002). "Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil." Clin Neuropharmacol 25(2): 111-4.
SUMMARY: Excessive daytime sleepiness (EDS) may limit the symptomatic treatment of Parkinson's disease and can alter the patient's lifestyle significantly. Ten consecutive patients with Parkinson's disease on various dopaminergic drugs and EDS were recruited to a 4-week open-label trial of modafinil. Patients were evaluated using the Epworth Sleepiness Scale and Unified Parkinson's Disease Rating Scale part III. All but three patients, with previous history of intolerability of a dopamine agonist caused by EDS, remained on their baseline medications. Modafinil was titrated as needed to a maximum of 400 mg/day. The mean Epworth Sleepiness Scale score at baseline of patients completing the study (n = 9) was 14.22 (+/- 3.03). After completing the study on an average dose of 172 mg/day, the Epworth Sleepiness Scale score was 6.0 (+/- 4.87). Unified Parkinson's Disease Rating Scale scores were not affected by this medication. Side effects encountered were headache, generalized paresthesias, and hallucinations (n = 1 each, the patient developing hallucinations dropped out of the trial before completing 4 weeks of the study drug). The three patients who did not tolerate any increments of dopamine agonist before modafinil were able to tolerate further upward titration of the dopamine agonist. Modafinil may be effective in reducing EDS in patients with Parkinson's disease treated with dopaminergic drugs. It does not seem to worsen parkinsonian symptoms and may allow further increase in dopaminergic therapy in patients previously unable to tolerate this because of EDS.

Nyholm, D., H. Lennernas, et al. (2002). "Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations." Clin Neuropharmacol 25(2): 89-96.
Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 microg/mL and peak concentrations between 0.95 to 13.75 microg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

Olanow, C. W. (2002). "The role of dopamine agonists in the treatment of early Parkinson's disease." Neurology 58(4 Suppl 1): S33-41.
Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). However, chronic treatment is associated with development of motor complications in the majority of patients. Recent laboratory studies suggest that pulsatile administration of a short-acting agent, such as levodopa, contributes to the development of these problems and that they might be mitigated through the use of longer-acting dopamine agonists. Placebo-controlled clinical trials have shown that dopamine agonists have anti-parkinsonian effects in patients with early PD. More importantly, four different prospective double-blind studies have demonstrated that initiating symptomatic therapy with a dopamine agonist is associated with a significantly reduced risk for development of motor complications than is initial treatment with a dopamine agonist. Furthermore, several lines of laboratory research suggest that dopamine agonists might protect dopaminergic neurons in PD and retard the rate of disease progression. Double-blind trials using clinical and imaging end points are now testing this hypothesis and the results should soon be available. On the basis of this evidence, a rational approach to the treatment of PD patients who are not elderly or cognitively impaired is to initiate therapy with a dopamine agonist and supplement with levodopa when dopamine agonist monotherapy can no longer provide satisfactory clinical control.

Ottaviani, E., A. J. Nappi, et al. (2002). "Resistance of the insect cell line IPLB-LdFB to salsolinol-induced apoptosis." Arch Insect Biochem Physiol 49(1): 1-9.
Apoptosis is a form of cell death that is manifested in Parkinson's disease (PD) and certain other neurodegenerative disorders. Metabolites of salsolinol (SAL), an intraneuronal, dopamine-derived tetrahydroisoquinoline (TIQ), have been shown to induce apoptosis in human dopaminergic neuroblastoma cells, implicating these molecules as causative or contributory factors in the selective killing of nigrostriatal dopaminergic neurons, a cardinal manifestation of Parkinson's disease. Since insects employ dopamine and related catecholamines in a variety of processes including cuticular sclerotization and cellular immune reactions, it was of interest to know how insect cells metabolized exogenous SAL. Propidium iodide staining combined with flow cytometry showed that IPLB-LdFB cells from Lymantria dispar exhibited no significant (P < 0.05) increase in apoptosis when incubated for 48 h with concentrations of SAL ranging from 10 microM to 1 mM. A significant increase in apoptosis (P < 0.05) was observed in cell cultures containing the highest concentration of SAL tested (5 mM), but only 12.4% of the cells manifested this form of cell death. High pressure liquid chromatography with electrochemical detection (HPLC-ED) was used to document the production of two potentially cytotoxic quinonoids generated during the autoxidation of SAL, a reaction that was found to be significantly (P < 0.05) enhanced by peroxidase. The resistance of IPLB-LdFB cells to SAL-induced apoptosis is attributed to the ability of these insect cells to metabolize and/or detoxify such dopamine-derived catecholic TIQs. Thus, the biochemical pathways employed by insect cells in these processes may be of considerable interest to individuals investigating certain neurodegenerative disorders.

Overstall, P. W. and C. E. Clarke (2002). "Uncertainties in the pharmacotherapy of Parkinson's disease and how to solve them." Gerontology 48(1): 30-3.
The causative relationship between levodopa and the long-term motor complications of therapy, along with the possibility that levodopa may be toxic to dopaminergic neurones in vivo, has led to a move away from its use in early Parkinson's disease. Alternatives such as amantadine and the anticholinergics suffer from poor efficacy in comparison and a high side effect profile. Selegiline is probably less effective than levodopa and the issue of its safety versus neuroprotective properties remains unresolved. Long-term trials with the old and newer dopamine agonists as monotherapy have shown that as a class they can delay the development of dyskinesia and probably response fluctuations. However, major uncertainties remain about their use as monotherapy in all patients instead of levodopa. No data on their effect on quality of life and health care costs are available. Most of the trials were heavily biased towards younger patients with Parkinson's disease, so little data in the elderly are available. In later disease when patients have already developed motor complications on levodopa, the choice rests between adjuvant therapy with a dopamine agonist, a catechol-O-methyltransferase inhibitor (COMT; e.g. entacapone), and a monoamine oxidase B inhibitor (MAO B; e.g. selegiline). Trials with the former two classes have confirmed that they can reduce 'off' time, reduce levodopa dose, and improve motor impairments and disabilities with acceptable increases in adverse events including dyskinesia. Trials with selegiline as adjuvant therapy were less rigorous but it can allow a reduction in levodopa dose and motor impairments. No studies have compared these three classes of drug as adjuvant therapy so there is no evidence on which to base rational decisions in this type of patient. A large pragmatic trial which includes older patients is needed to clarify which treatment is best for different stages of the disease.

Pekkone, E., J. Hirvonen, et al. (2002). "Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study." Neuroreport 13(1): 177-81.
Auditory P50 and N100 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated.The amplitude and latency changes of the electric and magnetic P50 and N100 were insignificant. Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison.

Pendleton, R. G., F. Parvez, et al. (2002). "Effects of pharmacological agents upon a transgenic model of Parkinson's disease in Drosophila melanogaster." J Pharmacol Exp Ther 300(1): 91-6.
The human gene that codes for the protein alpha-synuclein has been transferred into the Drosophila melanogaster genome. The transgenic flies recapitulate some of the essential features of Parkinson's disease. These include the degeneration of certain dopaminergic neurons in the brain accompanied by the appearance of age-dependent abnormalities in locomotor activity. In the present study, we tested the locomotor response of these transgenic flies to prototypes of the major classes of drugs currently used to treat this disorder. A time course study was first conducted to determine when impaired locomotor activity appeared relative to normal "wild-type" flies. A climbing or negative geotaxis assay measuring the ability of the organisms to climb up the walls of a plastic vial was used. Based on the results obtained, normal and transgenic flies were treated with each of the drugs in their food for 13 days and then assayed. The activity of transgenic flies treated with L-DOPA was restored to normal. Similarly, the dopamine agonists pergolide, bromocriptine, and 2,3,4,5-tetrahydro-7,8-dihydroxy- 1-phenyl-1H-3-benzazepine (SK&F 38393) were substantially effective. Atropine, the prototypical muscarinic cholinergic receptor antagonist, was also effective but to a lesser extent than the other antiparkinson compounds. p-Chlorophenylalanine, an inhibitor of serotonin synthesis, was without beneficial effect as was alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis. This behavioral study further demonstrates the utility of this model in studying Parkinson's disease and reinforces the concept that inhibition of the action of alpha-synuclein may be useful in its treatment as may dopamine D(1) receptor agonists.

Perez, R. G., J. C. Waymire, et al. (2002). "A role for alpha-synuclein in the regulation of dopamine biosynthesis." J Neurosci 22(8): 3090-9.
The alpha-synuclein gene is implicated in the pathogenesis of Parkinson's disease. Although alpha-synuclein function is uncertain, the protein has homology to the chaperone molecule 14-3-3. In addition, alpha-synuclein can bind to 14-3-3, and both alpha-synuclein and 14-3-3 bind to many of the same proteins. Because 14-3-3 binds to and activates tyrosine hydroxylase, the rate-limiting enzyme in dopamine (DA) biosynthesis, we explored whether alpha-synuclein also bound to tyrosine hydroxylase and influenced its activity. Immunoprecipitation revealed an interaction between alpha-synuclein and tyrosine hydroxylase in brain homogenates and MN9D dopaminergic cells. Colocalization of alpha-synuclein with tyrosine hydroxylase was confirmed by immunoelectron microscopy. To explore the consequences of the interaction, we measured the effect of recombinant alpha-synuclein on tyrosine hydroxylase activity in a cell-free system and observed a dose-dependent inhibition of tyrosine hydroxylase by alpha-synuclein. To measure the impact of alpha-synuclein on tyrosine hydroxylase in dopaminergic cells, we stably transfected MN9D cells with wild-type or A53T mutant alpha-synuclein. Overexpression of wild-type or A53T mutant alpha-synuclein did not significantly alter tyrosine hydroxylase protein levels in our stably transfected cells. However, overexpressing cell lines had significantly reduced tyrosine hydroxylase activity and a corresponding reduction in dopamine synthesis. The reduction in cellular dopamine levels was not caused by increased dopamine catabolism or dopamine efflux. These data suggest that alpha-synuclein plays a role in the regulation of dopamine biosynthesis, acting to reduce the activity of tyrosine hydroxylase. If so, a loss of soluble alpha-synuclein, by reduced expression or aggregation, could increase dopamine synthesis with an accompanying increase in reactive dopamine metabolites.

Pirker, W., S. Djamshidian, et al. (2002). "Progression of dopaminergic degeneration in Parkinson's disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study." Mov Disord 17(1): 45-53.
Atypical parkinsonian syndromes (APS) such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration are characterized by poor response to antiparkinsonian medication and rapid clinical deterioration. We used SPECT and [123I]beta-CIT as a label of dopamine transporters to study the progression of presynaptic dopaminergic degeneration in Parkinson's disease (PD) and APS. Twenty-four PD patients with short disease duration (2.4 +/- 1.5 years), 12 PD patients with long disease duration (9.2 +/- 2.6 years), 10 patients with APS (disease duration 2.1 +/- 1.5 years), and nine patients with essential tremor (ET) underwent sequential [123I]beta-CIT SPECT imaging with an interval of 25.5 +/- 10.3 (13-63) months. The age-related decline of striatal beta-CIT binding was studied cross-sectionally in 30 healthy subjects. The ratio of striatum/cerebellum -1 at 20 hours after tracer injection, reflecting specific-to-nondisplaceable binding, was used as the primary SPECT outcome measure. At scan 1, striatal beta-CIT binding was reduced in PD patients with short disease duration (-42% compared with age-corrected normal values) and long disease duration (-51%), and APS (-36%), but normal in ET. During the observation period striatal beta-CIT binding significantly declined in patients with APS (14.9% per year) and short duration PD (7.1% per year), whereas PD patients with long disease duration and patients with ET showed no significant change of striatal beta-CIT binding between scans 1 and 2. The relative annual reduction from age-corrected normal values at the time of scan 1 was significantly higher in patients with APS than in PD patients with short disease duration (9.6 vs. 4.3%, P = 0.004). These results demonstrate a rapid decline of striatal beta-CIT binding in patients with atypical parkinsonian syndromes, exceeding the reduction in PD. The dopaminergic degeneration in PD appears to slow down during the course of the disease. SPECT with [123I]beta-CIT is a sensitive marker of disease progression in parkinsonian disorders.

Ribeiro, M. J., M. Vidailhet, et al. (2002). "Dopaminergic function and dopamine transporter binding assessed with positron emission tomography in Parkinson disease." Arch Neurol 59(4): 580-6.
BACKGROUND: Measuring progression of Parkinson disease (PD) using positron emission tomography may help demonstrate the efficacy of neuroprotective treatments. To date, (18)F-dopa has been the gold standard to measure presynaptic dopaminergic function in PD, but this tracer might overestimate the rate of neuronal death in PD because its uptake also depends on dopamine turnover rather than exclusively on the density of dopaminergic terminals in the striatum. The latter might be assessed using newly developed ligands of the membrane dopamine transporter. OBJECTIVE: To compare the striatal uptakes of (18)F-dopa and (76)Br-FE-CBT, a dopamine transporter ligand, in patients with PD. PATIENTS AND METHODS: The striatal uptakes of (76)Br-FE-CBT and (18)F-dopa were compared using positron emission tomography in 10 patients with early PD and 8 with advanced PD. Correlation of uptakes with motor performance was investigated. RESULTS: The reduction in (76)Br-FE-CBT binding to 43% of control values was more severe than the reduction in (18)F-dopa uptake (63% of control values) in the putamen of patients with early PD. No significant difference was found between either tracer's uptake in the putamen of patients with advanced PD. Motor performance was highly correlated to (18)F-dopa uptake, whereas correlation to (76)Br-FE-CBT binding was weak. CONCLUSIONS: Uptake of (18)F-dopa may be up-regulated in early PD, suggesting a compensatory increase of dopamine synthesis in surviving dopaminergic terminals. Positron emission tomography dopamine transporter ligands and (18)F-dopa give complementary information on the presynaptic status of the nigrostriatal dopaminergic system and might be associated to investigate the efficacy of neuroprotective treatments in PD.

Riobo, N. A., F. J. Schopfer, et al. (2002). "The reaction of nitric oxide with 6-hydroxydopamine: implications for Parkinson's disease." Free Radic Biol Med 32(2): 115-21.
Oxidation of catecholamines is suggested to contribute to oxidative stress in Parkinson's disease. Nitric oxide (*NO) is able to oxidize cyclic compounds like ubiquinol; moreover, recent lines of evidence proposed a direct role of *NO and its by-product peroxynitrite in the pathophysiology of Parkinson's disease. The aim of this study was to analyze the potential reaction between 6-hydroxydopamine, a classic inducer of Parkinson's disease, and *NO. The results showed that *NO reacts with the deprotonated form of 6-hydroxydopamine at pH 7 and 37 degrees C with a second-order rate constant of 1.5 x 10(3) M(-1) x s(-1) as calculated by the rate of *NO decay measured with an amperometric sensor. Accordingly, the rates of formation of 6-hydroxy-dopamine quinone were dependent on *NO concentration. The coincubation of *NO and 6-hydroxydopamine with either bovine serum albumin or alpha-synuclein led to tyrosine nitration of the protein, in a concentration dependent-manner and sensitive to superoxide dismutase. These findings suggest the formation of peroxynitrite during the redox reactions following the interaction of 6-hydroxydopamine with *NO. The implications of this reaction for in vivo models are discussed in terms of the generation of reactive nitrogen and oxygen species within a propagation process that may play a significant role in neurodegenerative diseases.

Rye, D. B. and J. Jankovic (2002). "Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD." Neurology 58(3): 341-6.

Schapira, A. H. (2002). "Neuroprotection and dopamine agonists." Neurology 58(4 Suppl 1): S9-S18.
Several factors are known to be capable of inducing relatively selective dopaminergic cell death in the substantia nigra and inducing the clinical features that characterize Parkinson's disease (PD). Neuronal toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce parkinsonism in human and animal models, and rotenone, another specific mitochondrial complex I inhibitor, can induce similar effects in rodents to produce a model for PD. Studies in twins suggest a significant genetic component to young-onset PD, and several gene mutations have now been identified as causing familial autosomal dominant or autosomal recessive PD. Etiologic factors including free radical-mediated damage (including excitotoxicity), mitochondrial dysfunction, and inflammation-mediated cell damage can contribute to pathogenesis. In addition, the recent interest in protein misfolding, aggregation, and proteosomal activity has provided further insight into potential pathogenetic pathways in PD. Against this background there has been increasing interest in the development of drugs to modify these biochemical abnormalities and thus alter the course of PD, either by retarding the rate of cell death or by restoring function to neurons that are likely to be damaged but not dead. In this context, dopamine agonists have shown significant promise. Not only do these drugs provide symptomatic relief of PD but they also appear to be associated with a significant decrease in the rate of motor complications and to be capable of protecting against some of the adverse consequences of levodopa use. However, evidence is now emerging that dopamine agonists may have additional neuroprotective properties. As a group, they have antioxidant actions in vitro and in vivo. More specifically, the D(2)/D(3) dopamine agonist pramipexole may have neuroprotective activity that is, at least in part, unrelated to its dopamine agonist action. Protection in cell and animal models against a variety of toxins, including MPTP and 6-hydroxydopamine, confirms that this agonist has in vitro and in vivo neuroprotective action. Evidence is now emerging that some of this may be mediated by direct action on mitochondrial membrane potential and the inhibition of apoptosis. If the neuroprotective action of this drug is confirmed in patients with PD, this will have important implications for its early use in patients.

Schneider, J. S., M. Giardiniere, et al. (2002). "Effects of the prolyl endopeptidase inhibitor S 17092 on cognitive deficits in chronic low dose MPTP-treated monkeys." Neuropsychopharmacology 26(2): 176-82.
A number of neuropeptides are affected in Parkinson's disease and the enzyme proline endopeptidase contributes to the degradation of many of these neuropeptides, some of which are linked to a variety of cognitive functions. In the present study, the effects of the highly potent proline endopeptidase inhibitor S 17092 on cognitive deficits in monkeys induced by chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were examined. Chronic low dose MPTP administration resulted in deficits in performance of variable delayed response, delayed matching-to-sample, and delayed alternation tasks. Seven day oral administration of S 17092 followed by single dose administration of the same dose on the day of testing significantly improved overall performance on these tasks. The most effective dose of S 17092 was 3 mg/kg. These results indicate that S 17092 has cognition-enhancing properties in this model of early parkinsonism.

Seeman, P. and B. Madras (2002). "Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis." Behav Brain Res 130(1-2): 79-83.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2--0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.

Silverdale, M. A., A. R. Crossman, et al. (2002). "Striatal AMPA receptor binding is unaltered in the MPTP-lesioned macaque model of Parkinson's disease and dyskinesia." Exp Neurol 174(1): 21-8.
Long-term levodopa or dopamine agonist treatment in the MPTP-lesioned primate model of Parkinson's disease elicits dyskinesia, which is phenotypically similar to levodopa-induced dyskinesia in patients with Parkinson's disease. AMPA receptor antagonists have previously been shown to have both anti-parkinsonian and anti-dyskinetic actions in MPTP-lesioned primates, suggesting that AMPA receptor transmission is functionally overactive under these conditions. In this study, we investigated the level of striatal AMPA receptor binding in the MPTP lesioned primate using the selective AMPA ligand (3)H-(S)-5-fluorowillardiine. AMPA receptor binding was studied in non-parkinsonian, non-dyskinetic parkinsonian, and dyskinetic macaques. Striatal AMPA receptor binding was not different in any of the treatment groups (P > 0.05). Although AMPA receptor-mediated transmission is functionally overactive in Parkinson's disease and dyskinesia, changes in striatal AMPA receptor levels are not likely to be the cause of such movement disorders.

Singh, A. and S. K. Kulkarni (2002). "Nitecapone and selegiline as effective adjuncts to L-DOPA in reserpine-induced catatonia in mice." Methods Find Exp Clin Pharmacol 24(1): 23-9.
Reserpine-induced catatonia is a widely accepted animal model of Parkinson's disease. In the present study, reserpine (5 mg/kg i.p.) and alpha-methylpara-tyrosine (AMPT) (200 mg/kg i.p.) induced catatonia in mice 20 h and 1 h before the experiment, respectively, as assessed using the rota-rod and bar tests after reserpine treatment. There was a significant decrease in fall-off time in the rota-rod test and a significant increase in time spent on the bar in the bar test as compared to the untreated control mice. Combination therapy with L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) was less effective in reversing catatonia as compared to higher doses of L-DOPA (200 mg/kg i.p.) and carbidopa (20 mg/kg i.p.), which showed intense hyperactivity in reserpinized mice. Pretreatment with nitecapone (30 mg/kg i.p.), a COMT inhibitor, or selegiline (10 mg/kg i.p.), a MAO-B inhibitor potentiated the motor stimulant actions of subthreshold doses of the L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) combination. Amantadine (40 mg/kg i.p.), but not bromocriptine, potentiated the effects of L-DOPA treatment. The NMDA antagonistic action of amantadine may have beneficial effects. It is concluded that COMT and MAO-B enzymes play an important role in the metabolism of dopamine and administration of a COMT or MAO-B inhibitor may prove to be a better adjunct to L-DOPA therapy than a dopamine receptor agonist in Parkinson's disease.

Smolnik, R., S. Fischer, et al. (2002). "Brain potential signs of slowed stimulus processing following cholecystokinin in Parkinson's disease." Psychopharmacology (Berl) 161(1): 70-76.
RATIONALE: Cholecystokinin (CCK) is a neuropeptide which is colocalized with dopamine (DA) in neurons of the mesolimbic-frontocortical and nigrostriatal DA system. In animals CCK enhances DA activity in these systems. OBJECTIVES: The present study examined the effects of a single intranasal administration of CCK-8 on auditory brain potential (AEP) signs of cognitive processing and on motor performance in patients with Parkinson's disease (PD), known to originate from degeneration of DA neurons primarily in the nigrostriatal DA system. METHODS: Thirteen PD patients were examined after medication withdrawal, on two occasions after administration of placebo and 25 &mgr;g CCK-8, and compared with healthy controls matched for age and sex. AEPs were recorded while subjects performed an attention task (oddball paradigm). RESULTS: In the placebo condition, AEPs in the PD patients did not show marked alteration but were rather comparable to those in the controls. In healthy controls, CCK-8 enhanced the P3 complex ( P<0.05) and shortened latencies of the N2 and P3 components of the AEP evoked by task relevant target stimuli ( P<0.05). Contrary to expectations, in PD patients these AEP components were distinctly delayed after CCK-8 ( P<0.05). Motor performance was not changed by CCK-8 in PD patients or in controls. CONCLUSION: Data indicate a deleterious rather than beneficial effect of CCK on cognitive processing in PD patients that might result from a prevailing effect of the neuropeptide on transmitter systems (e.g. GABAergic) other than the DA system.

Sossi, V., R. de La Fuente-Fernandez, et al. (2002). "Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data." J Cereb Blood Flow Metab 22(2): 232-9.
An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.

Stefani, A., A. Bassi, et al. (2002). "Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the 'indirect pathway'." Clin Neurophysiol 113(1): 91-100.
OBJECTIVES: Previous studies suggested that the hypo-activity of the external pallidus (GPe) might drive the hyper-activity of subthalamic neurons, which underlies the cardinal symptoms of Parkinson's disease. We have challenged this view, based on the so-called 'indirect pathway', by recording apomorphine effects from both structures of parkinsonian patients, at rest and during passive movements. METHODS: We performed single-unit recordings from external pallidus (GPe), internal pallidus (GPi) and subthalamic nucleus (STN) during the stereotactic neurosurgery aimed to implant deep brain stimulating electrodes in GPi or STN. First, we verified the firing frequency of each structure in off-state conditions. Then, therapeutic, subdyskinetic concentrations of the dopaminergic agonist apomorphine was delivered to assess each nucleus response. RESULTS: The firing rate of STN averaged about 40 Hz; a large proportion (75%) of STN units exhibited marked responsiveness to passive movements. Apomorphine reduced the firing discharge of parkinsonian STN in all cells, although electrophysiological recovery was usually incomplete. Movement-related activity was also dramatically reduced. In contrast, apomorphine failed to modify the firing frequency of GPe, despite the amelioration of hypo-kinetic symptoms and the simultaneous inhibition of GPi firing discharge. CONCLUSIONS: We demonstrate that part of the models on basal ganglia circuitry needs to be revised. The re-balancing of STN hyper-activity, when patients benefit from dopaminergic therapy, is not due to an increased input from GPe, but, instead, due to changes in STN intrinsic firing properties and/or modulation of glutamatergic inputs.

Storch, A., S. Ott, et al. (2002). "Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter." Biochem Pharmacol 63(5): 909-20.
Endogenous isoquinoline (IQ) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>te trahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-M e-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.

Tabamo, R. E. and A. Di Rocco (2002). "Alopecia induced by dopamine agonists." Neurology 58(5): 829-30.

Tarsy, D., R. J. Baldessarini, et al. (2002). "Effects of newer antipsychotics on extrapyramidal function." CNS Drugs 16(1): 23-45.
Following acceptance of clozapine as a superior antipsychotic agent with low risk of adverse extrapyramidal syndromes (EPS), such as dystonia, parkinsonism, akathisia or tardive dyskinesia, several novel antipsychotic drugs have been developed with properties modelled on those of clozapine. Though generally considered 'atypical' in their relatively low risk of inducing EPS, these agents vary considerably in their pharmacology and impact on neurological functioning. Although few comparative data are available, the atypical antipsychotics can be tentatively ranked by EPS risk (excluding akathisia and neuroleptic malignant syndrome) in the following order: clozapine < quetiapine < olanzapine = ziprasidone. At higher doses, risperidone is ranked with a higher EPS risk than olanzapine and ziprasidone, but its risk of EPS is lower with lower doses. In general, this ranking is inversely related to antidopaminergic (D2 receptor) potency. The high antiserotonergic (5-HT2A receptor) potency of risperidone, clozapine, ziprasidone and olanzapine, but not quetiapine, as well as the antimuscarinic activity of olanzapine and clozapine may also limit EPS. For the treatment of psychotic reactions to dopamine agonist therapy in Parkinson's disease, clozapine is both effective and relatively well tolerated; quetiapine may be tolerated, olanzapine is not well tolerated, risperidone is poorly tolerated, and amisulpride and ziprasidone have not been well evaluated. Clozapine, perhaps because of its anticholinergic activity, can reduce parkinsonian tremor. It is useful for ongoing psychosis with tardive dyskinesia, especially for dystonic features. No atypical antipsychotic is clearly effective for motor abnormalities in Huntington's disease or Tourette's syndrome, and the effect of these drugs on other neurological disorders have been well evaluated in only small numbers of patients. In summary, with the exception of clozapine, and perhaps quetiapine, atypical antipsychotics have brought only relative avoidance of EPS, strongly encouraging continued searches for novel antipsychotic agents.

Tatsch, K. (2002). "Can SPET imaging of dopamine uptake sites replace PET imaging in Parkinson's disease?" Eur J Nucl Med 29(5): 711-4.

Thumen, A., A. Behnecke, et al. (2002). "N-methyl-norsalsolinol, a putative dopaminergic neurotoxin, passes through the blood-brain barrier in vivo." Neuroreport 13(1): 25-8.
In earlier studies the dihydroxylated tetrahydroisoquinoline derivatives salsolinol and 2(N)-methyl-norsalsolinol (NMNorsal), a 2(N)-analogue of salsolinol, were identified as putative endogenous neurotoxins in patients with Parkinson's disease. Since a prominent blood-brain barrier (BBB) was described to exist for salsolinol, in the present study microdialysis experiments were performed to investigate the penetration of NMNorsal through the BBB into the caudate nucleus of the rat brain. After i.p. administration of NMNorsal (20 mg/kg), it could be detected in the dialysate of the caudate nucleus with a mean maximum after 40 min. There was no alteration in extracellular dopamine or 3,4-dihydroxyphenylacetic acid levels. Addition of the monoamine oxidase inhibitor pargyline (10 microM) to the perfusate did not modify NMNorsal levels in the caudate nucleus. To corroborate the microdialysis results, homogenates of the contralateral caudate nucleus were prepared and NMNorsal could also be detected. These findings indicate that NMNorsal is indeed able to pass through the blood-brain barrier of the rat brain.

Trevitt, T., B. Carlson, et al. (2002). "Interactions between dopamine D1 receptors and gamma-aminobutyric acid mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies." Psychopharmacology (Berl) 159(3): 229-37.
RATIONALE: Several studies have shown that dopamine D1 agonists act on forebrain dopamine terminal regions to exert many of their behavioral effects. Yet, there is also a large number of D1 receptors in the substantia nigra pars reticulata (SNr), and these receptors are located mainly on terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. OBJECTIVE: The present studies were undertaken to determine the behavioral and neurochemical effects of local administration of the D1 agonist SKF 82958 and to study the interactions between D1 and GABA mechanisms in SNr. METHODS: Microdialysis methods were used to characterize the effect of SKF 82958 on extracellular GABA, and several experiments studied the effects of nigral D1 stimulation on motor activity and investigated the behavioral significance of D1/GABA interactions in SNr. RESULTS: Local infusion of 10(-6) M SKF 82958 increased extracellular levels of SNr GABA, and this effect was blocked by co-infusion of the D1 antagonist SCH 23390. Bilateral SNr injections of SKF 82958 increased locomotor activity, and this effect was blocked by the GABA-A antagonist bicuculline. Intranigral bicuculline reduced motor activity, while the GABA-A agonist muscimol increased various motor activities in a manner similar to SKF 82958. CONCLUSIONS: The present results suggest that the D1 agonist SKF 82958 acts on D1 receptors in SNr to increase extracellular levels of GABA, and the increase in motor activity produced by nigral D1 stimulation is dependent on stimulation of GABA-A receptors. D1/GABA interactions in SNr are important for the modulation of basal ganglia output, which may have important implications for Parkinson's disease.

Tsuboi, K. and C. W. Shults (2002). "Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease." Exp Neurol 173(1): 95-104.
Sonic hedgehog (Shh), a member of hedgehog (hh) family of signaling molecules, is necessary for normal axial patterning and cellular differentiation in the developing central nervous system. Shh also promotes the survival of fetal dopaminergic neurons and protects cultures of fetal midbrain dopaminergic neurons from the toxic effects of N-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that selectively injures nigral dopaminergic neurons. The mRNA expression of Shh and its putative receptor in the adult brain indicates an important role of Shh in the mature nervous system in addition to its roles during embryogenesis. In this study we examined the behavioral and anatomical effects of intrastriatal injection of singly myristoylated wild-type human Sonic hedgehog N-terminal fragment (Shh-M) in a rat model of Parkinson's disease (PD). Five groups of rats received a series of four intrastriatal injections of Shh-M (180 ng, 540 ng, or 4.275 microg per injection), glial cell line-derived neurotrophic factor (GDNF) (1 microg/injection), or vehicle on days 1, 3, 5, and 8. On day 4, the animals received an intrastriatal injection of 15 microg 6-hydroxydopamine (6-OHDA) free base. Intrastriatal administration of Shh (180 ng/injection) twice before and after a single intrastriatal injection of 6-OHDA reduced apomorphine- and amphetamine-induced rotation and forelimb akinesia and partially preserved dopaminergic axons in the striatum. This is the first demonstration in vivo that Shh reduces behavioral deficits induced by intrastriatal 6-OHDA lesion and suggests that Shh may be useful in the treatment of disorders that affect the nigrostriatal system, such as PD.

Uberti, D., L. Piccioni, et al. (2002). "Pergolide protects SH-SY5Y cells against neurodegeneration induced by H(2)O(2)." Eur J Pharmacol 434(1-2): 17-20.
We found that pergolide, a dopamine D1/D2 receptor agonist used in the clinical therapy of Parkinson's disease, protects SH-SY5Y neuroblastoma cells from cell death induced by a brief pulse (15 min) of 1 mM H(2)O(2). Neuroprotection was found when pergolide was added to the culture medium either simultaneously with (EC(50)=60 nM) or 2 h before (EC(50)=40 nM) H(2)O(2) treatment. These effects were not blocked by different dopamine receptor antagonists. Our data suggest that pergolide, independently of dopamine receptor stimulation, may interfere with the early phases of the oxidative stress-induced neurotoxic process.

Ulivelli, M., S. Rossi, et al. (2002). "Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD." Neurology 58(3): 462-5.
Both dopamine agonists and levodopa may induce episodes termed "sleep attacks" in patients with PD. These episodes are well detailed behaviorally, but little is known about their neurophysiologic characterization. The authors performed a 24-hour polysomnography (PSG) in a PD patient taking pergolide in combination with levodopa, in which four of these diurnal sleep episodes occurred. PSG findings were followed up after pergolide withdrawal. Sleep episodes shared with narcolepsy both behavioral and EEG findings. However, pergolide partly restored a more physiologic sleep architecture, which was disrupted during therapy with levodopa alone.

van de Vijver, D. A., R. A. Roos, et al. (2002). "Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users." Acta Neurol Scand 105(1): 8-12.
OBJECTIVES: Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson's disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Data came from the PHARMO database, which includes information on drug dispensing for all residents of six Dutch cities. Selected were all patients aged 55 years and older who used levodopa for at least 360 days. The rate of increase of antiparkinsonian drug treatment was compared between starters of a benzodiazepine and controls who did not start a benzodiazepine with the use of Cox's proportional hazard model. RESULTS: Identified were 45 benzodiazepine starters (27 women, mean age 76.4 years) and 169 controls (83 women, 74.3 years). Antiparkinsonian drug treatment increased faster in the benzodiazepine group; relative risk was 1.44 (95% confidence interval 0.80-2.59). CONCLUSION: This study has not found any statistically significant increase in antiparkinsonian drug treatment when a benzodiazepine was started in a small population of chronic levodopa users.

van Dyck, C. H., J. P. Seibyl, et al. (2002). "Age-related decline in dopamine transporters: analysis of striatal subregions, nonlinear effects, and hemispheric asymmetries." Am J Geriatr Psychiatry 10(1): 36-43.
Neuroimaging studies have documented an age-related decline in striatal dopamine transporters (DATs) as a marker of dopaminergic neurodegeneration. The authors further elucidated the effects on this neural system in healthy aging, in contrast to Parkinson disease (PD). The effects of age on striatal DAT availability were examined in a large, healthy subject sample (N=126) with [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT) and single photon emission computed tomography (SPECT). Striatal DAT availability (V3") showed a significant inverse correlation with age, declining in a nearly linear manner by 46% over the age range 18 to 88 years, or 6.6% per decade. Rates of decline were comparable for caudate (48%) and putamen (45%), with only minimal increase in left-right asymmetry with age. Hemispheric asymmetries were unrelated to the handedness of subjects. These results demonstrate that aging is associated with a relatively symmetric loss of DATs in the caudate and putamen in both hemispheres. These findings have implications not only for healthy aging but also for neurodegenerative disorders such as PD.

van Oosten, R. V. and A. R. Cools (2002). "Differential effects of a small, unilateral, 6-hydroxydopamine-induced nigral lesion on behavior in high and low responders to novelty." Exp Neurol 173(2): 245-55.
The goal of this study was to develop an animal model that evaluates striatal-specific behavior after partial, unilateral destruction of nigrostriatal neurons. 6-OHDA (1 microg) was injected intranigrally (day 0) to reduce dopaminergic innervation of the dorsal striatum (DS); 6-OHDA (5 microg) was injected to reduce innervation of DS and nucleus accumbens (ACC). We analyzed changes in (a) behavior regulated by dopamine (DA) release in the DS (hindpaw preference from day 5 to day 19, every other day) and the ACC (novelty-induced locomotion on day 16) and (b) apomorphine-induced rotation (on day 21). We used two types of rat that show differences in structure and function of the dopaminergic neurons, namely high (HR) and low (LR) responders to novelty. 6-OHDA (1 microg) significantly decreased TH immunoreactivity (TH-ir) in the DS and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. Only in LRs was the significant increase of novelty-induced locomotion accompanied by a significant increase in TH-ir density in the ACC: this suggests a lesion-induced shift in nigrostriatal/mesolimbic balance toward a dominance of the mesolimbic system. The higher 6-OHDA dose significantly decreased TH-ir in the DS and the ACC and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. However, this increase occurred significantly earlier in LRs than in HRs. Apomorphine elicited contralateral rotations solely in LRs, and not in HRs, indicating development of supersensitive dopamine receptors in the DS of LRs, but not HRs. The data show that LRs are more susceptible to 6-OHDA than HRs. The relevance of the present data for Parkinson's disease is discussed.

Wang, L., C. He, et al. (2002). "Effect of acupuncture on the auditory evoked brain stem potential in Parkinson's disease." J Tradit Chin Med 22(1): 15-7.
Under the auditory evoked brain stem potential (ABP) examination, the latent period of V wave and the intermittent periods of III-V peak and I-V peak were significantly shortened in Parkinson's disease patients of the treatment group (N = 29) after acupuncture treatment. The difference of cumulative scores in Webster's scale was also decreased in correlation analysis. The increase of dopamine in the brain and the excitability of the dopamine neurons may contribute to the therapeutic effects, in TCM terms, of subduing the pathogenic wind and tranquilizing the mind.

Wang, L., S. Muramatsu, et al. (2002). "Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease." Gene Ther 9(6): 381-9.
Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or beta-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD. DOI: 10.1038/sj/gt/3301682

Wittstock, M., R. Benecke, et al. (2002). "Cabergoline can increase penile erections and libido." Neurology 58(5): 831.

Wylie, S. A. and J. C. Stout (2002). "Enhanced negative priming in Parkinson's disease." Neuropsychology 16(2): 242-50.
In the ignored repetition paradigm, negative priming (NP) is defined as the increase in response time that occurs when the current target stimulus served as a distractor stimulus in the previous trial. In this study, 25 Parkinson's disease (PD) participants and 17 age-matched healthy controls (HCs) were tested using a touchscreen version of the ignored repetition task that allowed response time to be partitioned into response initiation and response execution segments. In both groups, NP effects were stronger in the response execution than in the response initiation segments. The most striking result was that the PD group showed larger NP effects overall than the HC group. In PD, clinical ratings of bradykinesia, but not tremor, were related to larger NP effects. Results indicate that in PD, disruption of dopamine neuromodulation diminishes response efficiency when action must be directed toward previously ignored information.

Yehuda, S. (2002). "Possible anti-Parkinson properties of N-(alpha-linolenoyl) tyrosine. A new molecule." Pharmacol Biochem Behav 72(1-2): 7-11.
Tyrosine is unable to cross the blood-brain barrier and is therefore unable to improve the status of brain dopamine (DA) and to provide relief for patients with Parkinson's disease (PD) or other DA-insufficient disorders. We report the creation of an amide bond molecule [N-(alpha-linolenoyl)tyrosine (NLT)] that combines tyrosine with a fatty acid mixture. NLT significantly improves the rotational behavior of rats [following unilateral striatal lesions (as a model for Parkinson's)] and overcomes the exaggerated eye-blinking induced by a potent DA-depleting agent (as a model for essential blepharospasm). These results are supported by the finding that NLT's mode of action, in striatum, is the same as the mode of action of D-amphetamine. They both induce an increase in the DA level, DA turnover and release.

Zappia, M., G. Annesi, et al. (2002). "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD." Neurology 58(5): 837; discussion 837-8.

 

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