(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 reduc