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Neuronal Injury Reviews
(48 References)
Albensi, B. C. and D. Janigro (2003). "Traumatic brain injury and its effects on synaptic plasticity." Brain Inj 17(8): 653-63.
Animal models have been used to simulate the effects of human head trauma. Some of these models have been further utilized to explore how trauma affects specific mechanisms of synaptic plasticity, a cellular model for memory consolidation. Unfortunately, these studies have been more limited in number in spite of their importance for understanding alterations in synaptic plasticity and memory impairments in trauma patients. Research in this area includes well characterized trauma models, genetically engineered animals and neuroprotective studies. One largely ignored but important idea that is entertained here is that trauma may be a crucial aetiological factor for the loss of potassium homeostasis. Moreover, high extracellular potassium has been shown to promote abnormal expression of hippocampal synaptic plasticity due to K(+)-induced glutamate release, thus showing important relationships among trauma, glia, potassium and synaptic plasticity. Collectively, this mini review surveys investigations of head trauma involving altered mechanisms of synaptic plasticity and how trauma may be related to increased risk for dementia.
Anderson, M. F., F. Blomstrand, et al. (2003). "Astrocytes and stroke: networking for survival?" Neurochem Res 28(2): 293-305.
Astrocytes are now known to be involved in the most integrated functions of the central nervous system. These functions are not only necessary for the normally working brain but are also critically involved in many pathological conditions, including stroke. Astrocytes may contribute to damage by propagating spreading depression or by sending proapoptotic signals to otherwise healthy tissue via gap junction channels. Astrocytes may also inhibit regeneration by participating in formation of the glial scar. On the other hand, astrocytes are important in neuronal antioxidant defense and secrete growth factors, which probably provide neuroprotection in the acute phase, as well as promoting neurogenesis and regeneration in the chronic phase after injury. A detailed understanding of the astrocytic response, as well as the timing and location of the changes, is necessary to develop effective treatment strategies for stroke patients.
Bach-y-Rita, P. (2003). "Theoretical basis for brain plasticity after a TBI." Brain Inj 17(8): 643-51.
Evidence has been accumulating that the brain can reorganize extensively after damage and that reorganization can be obtained even many years after the trauma with appropriate late rehabilitation. An understanding of the brain plasticity mechanisms should lead to more effective rehabilitation and neuropharmacology. In this communication, several emerging concepts with supporting experimental evidence have been presented. These include non-synaptic diffusion neurotransmission, extracellular space volume fraction, neurotransmitters, regeneration and neurogenesis and multiplexing.
Blomgren, K., C. Zhu, et al. (2003). "Mitochondria and ischemic reperfusion damage in the adult and in the developing brain." Biochem Biophys Res Commun 304(3): 551-9.
The developing and the adult brain respond in similar ways to ischemia, but also display clear differences. For example, the relative contributions of necrosis and apoptosis to neuronal death may be different, such that apoptotic mechanisms would be more prevalent in the developing brain. During normal development, more than half of the neurons in some brain regions are removed through apoptosis, and effectors like caspase-3 are highly upregulated in the immature brain. Mitochondria are pivotal regulators of cell death through their role in energy production and calcium homeostasis, their capacity to release apoptogenic proteins and to produce reactive oxygen species. This review will summarize some of the current studies dealing with mitochondria-related mechanisms of ischemic brain damage, with special reference to developmental aspects.
Browning, K. N. and D. Mendelowitz (2003). "Musings on the wanderer: what's new in our understanding of vago-vagal reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia." Am J Physiol Gastrointest Liver Physiol 284(1): G8-14.
To understand vago-vagal reflexes, one must have an appreciation of the events surrounding the encoding, integration, and central transfer of peripheral sensations by vagal afferent neurons. A large body of work has shown that vagal afferent neurons have nonuniform properties and that distinct subpopulations of neurons exist within the nodose ganglia. These sensory neurons display a considerable degree of plasticity; electrophysiological, pharmacological, and neurochemical properties have all been shown to alter after peripheral tissue injury. The validity of claims of selective recordings from populations of neurons activated by peripheral stimuli may be diminished, however, by the recent demonstration that stimulation of a subpopulation of nodose neurons can enhance the activity of unstimulated neuronal neighbors. To better understand the neurophysiological processes occurring after vagal afferent stimulation, it is essential that the electrophysiological, pharmacological, and neurochemical properties of nodose neurons are correlated with their sensory function or, at the very least, with their specific innervation target.
Burnett, A. L. (2003). "Neuroprotection and nerve grafts in the treatment of neurogenic erectile dysfunction." J Urol 170(2 Pt 2): S31-4; discussion S34.
PURPOSE: The rationale for protecting the nerve supply of the penis derives mainly from the fact that neurological injury or disease states involving this organ commonly result in erectile dysfunction. Novel directions in the management of neurogenic erectile dysfunction that pertain specifically to sustaining penile neuronal function are described. MATERIALS AND METHODS: The review constitutes a summary of neuroprotective strategies for penile erection that are under investigation at the basic science level or have been brought to clinical practice. The basic exercise consisted primarily of a literature search using the National Library of Medicine PubMed Services, with references made to such keywords as nerve grafts, nerve growth factors, neuroprotection and nerve regeneration. RESULTS: Primary advances in this field have centered on repairing structural defects and restoring the functional integrity of the cavernous nerves of the penis. In the former autologous nerve conduits, such as sural nerve grafts, have been explored and used prominently in the context of radical prostatectomy. In the latter diverse neurotrophic treatments have been investigated, with progress mostly limited to animal models of cavernous nerve injury. Basic concepts and ongoing developments in the neurobiology of axonal regeneration were identified as being applicable to this area of neurourology. CONCLUSIONS: Because neurogenic origins represent a leading categorical cause of erectile dysfunction, the importance of developing and applying treatment approaches to alleviate neuropathic effects on the erectile tissue of the penis is certain. Medical and surgical innovations for preserving and reconstituting the functional nerve supply of the penis offer great promise in the management of erectile dysfunction.
Calabresi, P., L. M. Cupini, et al. (2003). "Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia." Ann Neurol 53(6): 693-702.
Several new antiepileptic drugs (AEDs) have been introduced for clinical use recently. These new AEDs, as did the classic AEDs, target multiple cellular sites both pre- and postsynaptically. The major common goal of the pharmacological treatment using AEDs is to counteract abnormal brain excitability by either decreasing excitatory transmission or enhancing neuronal inhibition. Interestingly, an excessive release of excitatory amino acids and a reduced neuronal inhibition also occur in brain ischemia. Thus, recently, the use of AEDs as a possible neuroprotective strategy in brain ischemia is receiving increasing attention, and many AEDs have been tested in animal models of stroke, providing encouraging results. Experimental studies utilizing global or focal ischemia in rodents have provided insights into the possible neuroprotective action of the various AEDs. However, the implication of these studies in the treatment of acute stroke in humans is not always direct. In fact, various clinical studies with drugs targeting the same voltage- and ligand-gated channels modulated by most of the AEDs failed to show neuroprotection. The differential mechanisms that underlie the development of focal ischemic injury in experimental animal models versus human stroke require further investigation to open a new therapeutic perspective for neuroprotection that might be applicable in the future.
Carmichael, S. T. (2003). "Plasticity of cortical projections after stroke." Neuroscientist 9(1): 64-75.
Ischemic stroke produces cell death and disability, and a process of repair and partial recovery. Plasticity within cortical connections after stroke leads to partial recovery of function after the initial injury. Physiologically, cortical connections after stroke become hyperexcitable and more susceptible to the induction of LTP Stroke produces changes in the distribution and laterality of sensory, motor, and language representations within the brain that correlate with functional recovery. Anatomically, ischemic lesions induce axonal sprouting within local, intracortical projections and long distance, interhemispheric projections. This postischemic axonal sprouting establishes substantially new patterns of cortical connections with de-afferented or partially damaged brain areas. Axonal sprouting after ischemic lesions is induced by a transient pattern of synchronous, low-frequency neuronal activity in a network of cortical areas connected to the infarct. This pattern of neuronal activity that induces axonal sprouting in the adult after ischemic lesions resembles that seen in the developing brain during axonal elongation and synaptogenesis. Thus, stroke induces a process of remapping and reconnection within the adult brain through changes in neuronal activity that may involve a reactivation of developmental programs in areas connected to the infarct.
Chen, Y. and R. A. Swanson (2003). "Astrocytes and brain injury." J Cereb Blood Flow Metab 23(2): 137-49.
Astrocytes are the most numerous cell type in the central nervous system. They provide structural, trophic, and metabolic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions during brain ischemia and other insults can critically influence neuron survival. Astrocyte functions that are known to influence neuronal survival include glutamate uptake, glutamate release, free radical scavenging, water transport, and the production of cytokines and nitric oxide. Long-term recovery after brain injury, through neurite outgrowth, synaptic plasticity, or neuron regeneration, is influenced by astrocyte surface molecule expression and trophic factor release. In addition, the death or survival of astrocytes themselves may affect the ultimate clinical outcome and rehabilitation through effects on neurogenesis and synaptic reorganization.
Chernoff, E. A., D. L. Stocum, et al. (2003). "Urodele spinal cord regeneration and related processes." Dev Dyn 226(2): 295-307.
Urodele amphibians, newts and salamanders, can regenerate lesioned spinal cord at any stage of the life cycle and are the only tetrapod vertebrates that regenerate spinal cord completely as adults. The ependymal cells play a key role in this process in both gap replacement and caudal regeneration. The ependymal response helps to produce a different response to neural injury compared with mammalian neural injury. The regenerating urodele cord produces new neurons as well as supporting axonal regrowth. It is not yet clear to what extent urodele spinal cord regeneration recapitulates embryonic anteroposterior and dorsoventral patterning gene expression to achieve functional reconstruction. The source of axial patterning signals in regeneration would be substantially different from those in developing tissue, perhaps with signals propagated from the stump tissue. Examination of the effects of fibroblast growth factor and epidermal growth factor on ependymal cells in vivo and in vitro suggest a connection with neural stem cell behavior as described in developing and mature mammalian central nervous system. This review coordinates the urodele regeneration literature with axial patterning, stem cell, and neural injury literature from other systems to describe our current understanding and assess the gaps in our knowledge about urodele spinal cord regeneration.
Denicourt, C. and S. F. Dowdy (2003). "Protein transduction technology offers novel therapeutic approach for brain ischemia." Trends Pharmacol Sci 24(5): 216-8.
Transient or permanent reduction in cerebral blood flow following ischemia can lead to severe and irreversible tissue damage to the brain. Emerging biochemical evidence suggests a role for apoptosis in neuronal death following cerebral ischemia. Despite the abundance of studies on the subject, therapeutic interventions for ischemia-related cell injury have so far proved disappointing in clinical trials. Recently, four new, exciting studies reported the use of protein transduction technology to deliver anti-apoptotic molecules to protect neuronal cells following ischemic stroke in vivo. These studies offer new avenues for the treatment and prevention of cell death following brain injuries.
Dineley, K. E., T. V. Votyakova, et al. (2003). "Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration." J Neurochem 85(3): 563-70.
An increasing body of evidence suggests that high intracellular free zinc promotes neuronal death by inhibiting cellular energy production. A number of targets have been postulated, including complexes of the mitochondrial electron transport chain, components of the tricarboxylic acid cycle, and enzymes of glycolysis. Consequences of cellular zinc overload may include increased cellular reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and reduced cellular ATP levels. Additionally, zinc toxicity might involve zinc uptake by mitochondria and zinc induction of mitochondrial permeability transition. The present review discusses these processes with special emphasis on their potential involvement in brain injury.
Fern, R. (2003). "Variations in spare electron transport chain capacity: The answer to an old riddle?" J Neurosci Res 71(6): 759-62.
Several neurological diseases involve focal injury of specific brain structures. Poisons of the electron transport chain complexes (ETCC) can also produce selective injury of brain structures when given systemically and have been implicated in the development of neurological disease. Why ETCC poisons damage particular brain regions is unclear. Calculations of the relative ETCC expression level to glucose utilization rate (GUR) ratio from published observations here reveal that a low ETCC/GUR ratio predisposes a brain structure to injury by a poison of that complex. While GUR can rise with increased neuronal activity, ETCC expression is fixed in the short term. A high ETCC/GUR therefore represents surplus ETCC capacity, allowing for increased ATP generation with short-term increases in demand. A low ETCC/GUR indicates the opposite and will lead to energy failure when the specific ETCC is poisoned. These observations may explain why cyanide, a specific ETCC (IV) inhibitor, can produce selective injury of white matter, which has the lowest ETCC (IV)/GUR found in the brain. They are also consistent with the selective damage of the striatum produced by poisons such as rotenone, a form of injury implicated in Parkinson's disease. The striatum has a low ETCC (I)/GUR ratio, whereas rotenone is a selective ETCC (I) inhibitor.
Forster, H. V. (2003). "Plasticity in the control of breathing following sensory denervation." J Appl Physiol 94(2): 784-94.
The purpose of this manuscript is to review the results of studies on the recovery or plasticity following a denervation- or lesion-induced change in breathing. Carotid body denervation (CBD), lung denervation (LD), cervical (CDR) and thoracic (TDR) dorsal rhizotomy, dorsal spinal column lesions, and lesions at pontine, medullary, and spinal sites all chronically alter breathing. The plasticity after these is highly variable, ranging from near complete recovery of the peripheral chemoreflex in rats after CBD to minimal recovery of the Hering-Breuer inflation reflex in ponies after LD. The degree of plasticity varies among the different functions of each pathway, and plasticity varies with the age of the animal when the lesion was made. In addition, plasticity after some lesions varies between species, and plasticity is greater in the awake than in the anesthetized state. Reinnervation is not a common mechanism of plasticity. There is evidence supporting two mechanisms of plasticity. One is through upregulation of an alternate sensory pathway, such as serotonin-mediated aortic chemoreception after CBD. The second is through upregulation on the efferent limb of a reflex, such as serotonin-mediated increased responsiveness of phrenic motoneurons after CDR, TDR, and spinal cord injury. Accordingly, numerous components of the ventilatory control system exhibit plasticity after denervation or lesion-induced changes in breathing; this plasticity is uniform neither in magnitude nor in underlying mechanisms. A major need in future research is to determine whether "reorganization" within the central nervous system contributes to plasticity following lesion-induced changes in breathing.
Fukuda, S. and G. J. del Zoppo (2003). "Models of focal cerebral ischemia in the nonhuman primate." Ilar J 44(2): 96-104.
Ischemic stroke is a uniquely human disease syndrome. Models of focal cerebral ischemia developed in nonhuman primates provide clinically relevant platforms for investigating pathophysiological alterations associated with ischemic brain injury, microvascular responses, treatment responses, and clinically relevant outcomes that may be appropriate for ischemic stroke patients. A considerable number of advantages attend the use of nonhuman primate models in cerebral vascular research. Appropriate development of such models requires neurosurgical expertise to produce single or multiple vascular occlusions. A number of experimentally and clinically accessible outcomes can be measured, including neurological deficits, neuron injury, evidence of non-neuronal cell injury, infarction volume, real-time imaging of injury development, vascular responses, regional cerebral blood flow, microvascular events, the relation between neuron and vascular events, and behavioral outcomes. Nonhuman primate models of focal cerebral ischemia provide excellent opportunities for understanding the vascular and cellular pathophysiology of cerebral ischemic injury, which resembles human ischemic stroke, and the appropriate study of pharmacological interventions in a human relevant setting.
Goldstein, L. B. (2003). "Neuropharmacology of TBI-induced plasticity." Brain Inj 17(8): 685-94.
PRIMARY OBJECTIVE: The purpose of this report is to review both fundamental studies in laboratory animals and preliminary clinical data suggesting that certain drugs may affect behavioural recovery after brain injury. MAIN OUTCOMES AND RESULTS: Laboratory studies show that systemically-administered drugs that affect specific central neurotransmitters including norepinephrine and GABA influence affect recovery in a predictable manner. Although some drugs such as d-amphetamine have the potential to enhance recovery, others such as neuroleptics and other central dopamine receptor antagonists, benzodiazepines and the anti-convulsants phenytoin and phenobarbital may be detrimental. In one study, 72% of patients with traumatic brain injury received one or a combination of the drugs that may impair recovery based on both animal experiments and studies in recovering stroke patients. CONCLUSIONS: Until the true impact of these classes of drugs are better understood, care should be exercised in the use of medications that may interfere with the recovery process in patients with traumatic brain injury. Additional research needs to be completed before the clinical efficacy of drugs that may enhance recovery can be established.
Goshgarian, H. G. (2003). "The crossed phrenic phenomenon: a model for plasticity in the respiratory pathways following spinal cord injury." J Appl Physiol 94(2): 795-810.
Hemisection of the cervical spinal cord rostral to the level of the phrenic nucleus interrupts descending bulbospinal respiratory pathways, which results in a paralysis of the ipsilateral hemidiaphragm. In several mammalian species, functional recovery of the paretic hemidiaphragm can be achieved by transecting the contralateral phrenic nerve. The recovery of the paralyzed hemidiaphragm has been termed the "crossed phrenic phenomenon." The physiological basis for the crossed phrenic phenomenon is as follows: asphyxia induced by spinal hemisection and contralateral phrenicotomy increases central respiratory drive, which activates a latent crossed respiratory pathway. The uninjured, initially latent pathway mediates the hemidiaphragm recovery by descending into the spinal cord contralateral to the hemisection and then crossing the midline of the spinal cord before terminating on phrenic motoneurons ipsilateral and caudal to the hemisection. The purpose of this study is to review work conducted on the crossed phrenic phenomenon and to review closely related studies focusing particularly on the plasticity associated with the response. Because the review deals with recovery of respiratory muscles paralyzed by spinal cord injury, the clinical relevance of the reviewed studies is highlighted.
Graham, S. H. and R. W. Hickey (2003). "Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death." Arch Neurol 60(4): 628-30.
Hsueh, W., M. S. Caplan, et al. (2003). "Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts." Pediatr Dev Pathol 6(1): 6-23.
Necrotizing enterocolitis (NEC), a disease affecting predominantly premature infants, is a leading cause of morbidity and mortality in neonatal intensive care units. Although several predisposing factors have been identified, such as prematurity, enteral feeding, and infection, its pathogenesis remains elusive. In the past 20 years, we have established several animal models of NEC in rats and found several endogenous mediators, especially platelet-activating factor (PAF), which may play a pivotal role in NEC. Injection of PAF induces intestinal necrosis, and PAF antagonists prevent the bowel injury induced by bacterial endotoxin, hypoxia, or challenge with tumor necrosis factor-a (TNF) plus endotoxin in adult rats. The same is true for lesions induced by hypoxia and enteral feeding in neonatal animals. Human patients with NEC show high levels of PAF and decreased plasma PAF-acetylhydrolase, the enzyme degrading PAF. The initial event in our experimental models of NEC is probably polymorphonuclear leukocyte (PMN) activation and adhesion to venules in the intestine, which initiates a local inflammatory reaction involving proinflammatory mediators including TNF, complement, prostaglandins, and leukotriene C4. Subsequent norepinephrine release and mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Bacterial products (e.g., endotoxin) enter the intestinal tissue during local mucosal barrier breakdown, and endotoxin synergizes with PAF to amplify the inflammation. Reactive oxygen species produced by the activated leukocytes and by intestinal epithelial xanthine oxidase may be the final pathway for tissue injury. Protective mechanisms include nitric oxide produced by the constitutive (mainly neuronal) nitric oxide synthase, and indigenous probiotics such as Bifidobacteria infantis. The former maintains intestinal perfusion and the integrity of the mucosal barrier, and the latter keep virulent bacteria in check. The development of tissue injury depends on the balance between injurious and protective mechanisms.
Ikeda, K., H. Negishi, et al. (2003). "Antioxidant nutrients and hypoxia/ischemia brain injury in rodents." Toxicology 189(1-2): 55-61.
Cerebral ischemia and recirculation cause delayed neuronal death in rodents, such as Mongolian gerbils and stroke-prone spontaneously hypertensive rats (SHRSP), which were used as an experimental stroke model. It was documented that an enhanced nitric oxide production, the occurrence of apoptosis, and an attenuated redox regulatory system contribute to the development of delayed neuronal death. Many studies have suggested the beneficial antioxidant effects of antioxidant nutrients such as vitamin E, green tea extract, ginkgo biloba extract, resveratrol and niacin in cerebral ischemia and recirculation brain injury. These results are important in light of an attenuation of the deleterious consequences of oxidative stress in ischemia and recirculation injury.
Inamasu, J., Y. Nakamura, et al. (2003). "Induced hypothermia in experimental traumatic spinal cord injury: an update." J Neurol Sci 209(1-2): 55-60.
The use of induced hypothermia in the treatment of traumatic spinal cord injury (SCI) has been studied extensively between the 1960s and 1970s. Although the treatment showed some promise, it became less popular by the 1980s, mainly because of its adverse effects. However, a revival of hypothermia in the treatment of traumatic brain injury (TBI) in the last decade has encouraged neuroscientists to conduct experiments to reevaluate the potential benefits of hypothermia in traumatic SCI. All laboratory investigations studying the mechanisms of action and/or the efficacy of induced hypothermia in treating experimental traumatic SCI published in the last decade were reviewed. Although efficacy of hypothermia in improving functional outcome of mild to moderate traumatic SCI has been demonstrated, hypothermia may not be protective against severe traumatic SCI. At present, induced hypothermia has yet to be recognized or approved as a potential treatment having therapeutic value for traumatic SCI in humans. The continued search for a possible synergistic effect of induced hypothermia and pharmacological therapy may yield some promise. It has also been deduced from these laboratory studies that hyperthermia is deleterious and rigorous measures to prevent hyperthermia should be taken to minimize the propagation of secondary neuronal damage after traumatic SCI.
Kim, K. S. (2003). "Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury." Nat Rev Neurosci 4(5): 376-85.
Kolb, B. (2003). "Overview of cortical plasticity and recovery from brain injury." Phys Med Rehabil Clin N Am 14(1 Suppl): S7-25, viii.
The analysis of plastic changes in the nervous system is based on the assumption that the nervous system is not a static system but rather one that changes over time. Neural plasticity can be studied at many levels, beginning with behavior and then becoming progressively more microscopic by descending to the level of cerebral maps, synaptic organization, physiologic activities, molecular structure, and mitosis. This article considers each level in turn and then briefly describes how an understanding of the principles of plasticity can be used to initiate treatments for cerebral injury.
Kuroiwa, T. and R. Okeda (2003). "Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbance." Neuropathology 23(1): 79-89.
In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real-time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemia are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach.
Levin, H. S. (2003). "Neuroplasticity following non-penetrating traumatic brain injury." Brain Inj 17(8): 665-74.
The primary objective of this review is to examine the methodology and evidence for neuroplasticity operating in recovery from traumatic brain injury (TBI), as compared with previous findings in patients sustaining perinatal and infantile focal vascular lesions. The evidence to date indicates that the traditional view of enhanced reorganization of function after early focal brain lesions might apply to early focal brain lesions, but does not conform with studies of early severe diffuse brain injury. In contrast to early focal vascular lesions, young age confers no advantage in the outcome of severe diffuse brain injury. Disruption of myelination could potentially alter connectivity, a suggestion which could be confirmed through diffusion tensor imaging (DTI). Initial reports of DTI in TBI patients support the possibility that this technique can demonstrate alterations in white matter connections which are not seen on conventional magnetic resonance imaging (MRI) and might change over time or with interventions. Preliminary functional MRI studies of TBI patients indicate alterations in the pattern of brain activation, suggesting recruitment of more extensive cortical regions to perform tasks which stress computational resources. Functional MRI, coupled with DTI and possibly other imaging modalities holds the promise of elucidating mechanisms of neuroplasticity and repair following TBI.
Lythgoe, M. F., N. R. Sibson, et al. (2003). "Neuroimaging of animal models of brain disease." Br Med Bull 65: 235-57.
The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.
Maiese, K. and Z. Z. Chong (2003). "Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain." Trends Pharmacol Sci 24(5): 228-32.
Although usually identified as an essential cellular nutrient for cellular growth and maintenance, nicotinamide is under development as a novel cytoprotectant for acute and chronic neurodegenerative disorders. Here, we outline support for the premise that nicotinamide both prevents and reverses neuronal and vascular cell injury. Nicotinamide fosters DNA integrity and maintains phosphatidylserine membrane asymmetry to prevent cellular inflammation, cellular phagocytosis and vascular thrombosis. The downstream cellular and molecular cascades are considered vital for the cytoprotection offered by nicotinamide. These pathways encompass the modulation of Akt, the forkhead transcription factor FKHRL1, mitochondrial membrane potential, caspase activities and cellular energy metabolism, but remain independent of intracellular pH and mitogen-activated protein kinases. As both a therapeutic agent and an investigational tool, nicotinamide offers new therapeutic strategies for degenerative disorders of the CNS.
Marcus, A. J., M. J. Broekman, et al. (2003). "Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases." J Pharmacol Exp Ther 305(1): 9-16.
Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39-an ecto-ADPase-reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.
Mattson, M. P., W. Duan, et al. (2003). "Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms." J Neurochem 84(3): 417-31.
Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.
McGee, A. W. and S. M. Strittmatter (2003). "The Nogo-66 receptor: focusing myelin inhibition of axon regeneration." Trends Neurosci 26(4): 193-8.
CNS myelin inhibits axonal outgrowth in vitro and is one of several obstacles to functional recovery following spinal cord injury. Central to our current understanding of myelin-mediated inhibition are the membrane protein Nogo and the Nogo-66 receptor (NgR). New findings implicate NgR as a point of convergence in signal transduction for several myelin-associated inhibitors. Additional studies have identified a potential coreceptor for NgR as p75(NTR), and a second-messenger pathway involving RhoA that inhibits neurite elongation. Although these findings expand our understanding of the molecular determinants of adult CNS axonal regrowth, the physiological roles of myelin-associated inhibitors in the intact adult CNS remain ill-defined.
Mitchell, G. S. and S. M. Johnson (2003). "Neuroplasticity in respiratory motor control." J Appl Physiol 94(1): 358-74.
Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.
Morrison, R. S., Y. Kinoshita, et al. (2003). "p53-dependent cell death signaling in neurons." Neurochem Res 28(1): 15-27.
The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to multiple forms of cellular stress. p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from animal models and patients with chronic neurodegenerative diseases. p53 deficiency or p53 inhibition protects neurons from a wide variety of acute toxic insults. Signal transduction pathways associated with p53-induced neuronal cell death are being characterized, suggesting that intervention may prove effective in maintaining neuronal viability and restoring function following neural injury and disease.
Nudo, R. J., D. Larson, et al. (2003). "A squirrel monkey model of poststroke motor recovery." Ilar J 44(2): 161-74.
Nonhuman primate models of poststroke recovery have become increasingly rare primarily due to high purchase and maintenance costs and limited availability of nonhuman primate species. Despite this obstacle, nonhuman primate models may offer important advantages over rodent models for understanding many of the brain's mechanisms for self-repair due to greater similarity in cortical organization to humans. Since the mid-1990s, surgical, neurophysiological, and neuroanatomical methods have been developed to understand structural and functional remodeling of the cerebral cortex after an ischemic event, such as occurs in stroke. These methods require long surgical procedures and entail constant physiological monitoring. With careful attention to intraoperative and postsurgical monitoring, these procedures can be repeated multiple times in individual monkeys without untoward events. This model provides a statistically powerful approach for tracking brain plasticity in the ensuing weeks and months after a stroke-like injury, reducing the number of animals required for individual experiments. This methodology is described in detail, and many of the resulting findings that are relevant for understanding stroke recovery and the effects of rehabilitative and pharmacotherapeutic interventions are summarized.
Nudo, R. J. (2003). "Functional and structural plasticity in motor cortex: implications for stroke recovery." Phys Med Rehabil Clin N Am 14(1 Suppl): S57-76.
Several studies have now demonstrated that the motor cortical representations are dynamically maintained in both normal and brain-injured animals. Functional plasticity in the motor cortex of normal animals is accompanied by changes in synaptic morphology; these changes are skill-dependent rather than simply use-dependent. Finally, motor cortical areas undergo substantial functional alterations after focal ischemic infarcts; motor experience is a potent and adaptive modulator of injury-related plasticity. These recent neuroscientific advances set the stage for the development of new, more effective interventions in chronic stroke populations that are based on the basic mechanisms underlying neuroplasticity.
Patel, H. C., H. Boutin, et al. (2003). "Interleukin-1 in the brain: mechanisms of action in acute neurodegeneration." Ann N Y Acad Sci 992: 39-47.
Interleukin-1 (IL-1) exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. Much of this is based on studies using the IL-1 receptor antagonist, which inhibits cell death caused by ischemia, brain injury, or excitotoxins. Our aim is to determine how and where in the brain IL-1 acts to produce these effects. Most of the neurodegenerative effects of IL-1 are thought to be through IL-1 beta. However, we have data implicating IL-1 alpha in excitotoxic cell death. Furthermore mice lacking both IL-1 alpha and IL-1 beta show dramatically reduced ischemic cell death, whereas deletion of IL-1 alpha or IL-1 beta alone fails to modify damage. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of the type I IL-1 receptor, suggesting the existence of novel IL-1 receptors in the brain. IL-1 also dramatically exacerbates neuronal loss in response to intrastriatal administration of the excitotoxin AMPA in the rat brain, an effect accompanied by marked increases in cytokine expression in the frontoparietal cortex, which precedes subsequent cell death in this region. Intrastriatal AMPA also results in limbic seizures that are exacerbated by IL-1, and we hypothesize, therefore, that IL-1 exacerbates cell death through increased seizure activity. Therefore, IL-1 appears to induce acute neurodegeneration through a number of mechanisms.
Payne, J. A., C. Rivera, et al. (2003). "Cation-chloride co-transporters in neuronal communication, development and trauma." Trends Neurosci 26(4): 199-206.
Electrical signaling in neurons is based on the operation of plasmalemmal ion pumps and carriers that establish transmembrane ion gradients, and on the operation of ion channels that generate current and voltage responses by dissipating these gradients. Although both voltage- and ligand-gated channels are being extensively studied, the central role of ion pumps and carriers is largely ignored in current neuroscience. Such an information gap is particularly evident with regard to neuronal Cl- regulation, despite its immense importance in the generation of inhibitory synaptic responses by GABA- and glycine-gated anion channels. The cation-chloride co-transporters (CCCs) have been identified as important regulators of neuronal Cl- concentration, and recent work indicates that CCCs play a key role in shaping GABA- and glycine-mediated signaling, influencing not only fast cell-to-cell communication but also various aspects of neuronal development, plasticity and trauma.
Perez Velazquez, J. L., M. V. Frantseva, et al. (2003). "Gap junctions and neuronal injury: protectants or executioners?" Neuroscientist 9(1): 5-9.
The authors review concepts and recent experimental observations that relate gap junctional communication to the pathophysiology of neuronal injury, specifically ischemic or traumatic damage. The role played by this type of direct intercellular communication during the progression of the injuries can be conceived to be either detrimental or beneficial, depending on the arguments employed. The data indicate that, far from being a simple matter of judgment, the contribution of gap junctions to cell injury is a complicated phenomenon that depends on the specific insult and network in which it operates.
Powner, D. J. (2003). "Effects of gene induction and cytokine production in donor care." Prog Transplant 13(1): 9-14; quiz 15-6.
Gene induction, cytokine production, and programmed neuronal and myocardial cell death are concerns that have entered the areas of donor evaluation and care over the past several years. Following ischemic or traumatic brain injury and the evolution of brain death, a large number of proteins (cytokines) are produced as part of a regional inflammatory response. These cytokines and related compounds appear to contribute to programmed death (apoptosis) of individual cells and the severe cardiac and hemodynamic changes often encountered during donor care. In addition, these cytokines and related compounds may sensitize donor organs so that a faster and more severe form of rejection occurs in the recipient. Although no directed therapy for these cytokine effects is presently available, the organ procurement coordinator should be aware of these issues and concerns as new treatment options evolve in the near future.
Prins, M. L. and D. A. Hovda (2003). "Developing experimental models to address traumatic brain injury in children." J Neurotrauma 20(2): 123-37.
Traumatic brain injury (TBI) is the leading cause of injury-related death and disability among children under the age of 15 years in the United States. Epidemiological studies have revealed that even within the pediatric population there are differences in incidence, gender differences, causes, types of injuries sustained, and mortality within age subdivisions. This heterogeneity must be taken into account when developing appropriate models to address TBI in children. This review explores the current developmental TBI models, including fluid percussion, weight drop, and controlled cortical impact. It also addresses unique considerations to modeling pediatric brain injury that require special attention when modeling and designing studies: age appropriateness, injury severity, evaluation of recovery, plasticity, and anesthesia.
Ray, S. K., E. L. Hogan, et al. (2003). "Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors." Brain Res Brain Res Rev 42(2): 169-85.
Spinal cord injury (SCI) evokes an increase in intracellular free Ca(2+) level resulting in activation of calpain, a Ca(2+)-dependent cysteine protease, which cleaves many cytoskeletal and myelin proteins. Calpain is widely expressed in the central nervous system (CNS) and regulated by calpastatin, an endogenous calpain-specific inhibitor. Calpastatin degraded by overactivation of calpain after SCI may lose its regulatory efficiency. Evidence accumulated over the years indicates that uncontrolled calpain activity mediates the degradation of many cytoskeletal and membrane proteins in the course of neuronal death and contributes to the pathophysiology of SCI. Cleavage of the key cytoskeletal and membrane proteins by calpain is an irreversible process that perturbs the integrity and stability of CNS cells leading to cell death. Calpain in conjunction with caspases, most notably caspase-3, can cause apoptosis of the CNS cells following trauma. Aberrant Ca(2+) homeostasis following SCI inevitably activates calpain, which has been shown to play a crucial role in the pathophysiology of SCI. Therefore, calpain appears to be a potential therapeutic target in SCI. Substantial research effort has been focused upon the development of highly specific inhibitors of calpain and caspase-3 for therapeutic applications. Administration of cell permeable and specific inhibitors of calpain and caspase-3 in experimental animal models of SCI has provided significant neuroprotection, raising the hope that humans suffering from SCI may be treated with these inhibitors in the near future.
Rivest, S. (2003). "Molecular insights on the cerebral innate immune system." Brain Behav Immun 17(1): 13-9.
All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.
Rothwell, N. (2003). "Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential." Brain Behav Immun 17(3): 152-7.
Interleukin-1 (IL-1) expression in the brain increases in response to acute and chronic insults, and IL-1 contributes directly to experimentally induced ischaemic, excitotoxic, and traumatic brain injury. Release and cleavage of active IL-1 beta may be achieved via purinergic P2X7 receptors and activation of caspase-1. The mechanisms of action of IL-1 are largely unknown, but may involve effects on glia, endothelia, and neurones, or on physical parameters within the brain such as temperature or acidity. The naturally occurring IL-1 receptor antagonist (IL-1ra) is currently being considered for treatment of stroke and other disorders.
Sawynok, J. and X. J. Liu (2003). "Adenosine in the spinal cord and periphery: release and regulation of pain." Prog Neurobiol 69(5): 313-40.
In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
Schallert, T., M. T. Woodlee, et al. (2003). "Experimental focal ischemic injury: behavior-brain interactions and issues of animal handling and housing." Ilar J 44(2): 130-43.
In experimental neurological models of brain injury, behavioral manipulations before and after the insult can have a major impact on molecular, anatomical, and functional outcome. Investigators using animals for preclinical research should keep in mind that people with brain injury have lived in, and will continue to live in, an environment that is far more complex than that of the typical laboratory rodent. To yield more reliable and relevant behavioral assessment, it may be appropriate in some cases to house animals in environments that allow for motor enrichment and to handle animals in ways that promote tameness. Experience can affect mechanisms of plasticity and degeneration beneficially or adversely. Behavioral interventions that have been found to modulate postinjury brain events are reviewed. The timing and interaction of biological and motor therapies and the potential contribution of experience-dependent and drug-induced trophic factor expression are discussed.
Tang, B. L. (2003). "Inhibitors of neuronal regeneration: mediators and signaling mechanisms." Neurochem Int 42(3): 189-203.
Neuritogenesis and its inhibition are opposite and balancing processes during development as well as pathological states of adult neuron. In particular, the inability of adult central nervous system (CNS) neurons to regenerate upon injury has been attributed to both a lack of neuritogenic ability and the presence of neuronal growth inhibitors in the CNS environment. I review here recent progress in our understanding of neuritogenic inhibitors, with particular emphasis on those with a role in the inhibition of neuronal regeneration in the CNS, their signaling cascades and signal mediators. Neurotrophines acting through the tropomyosin-related kinase (Trk) family and p75 receptors promote neuritogenesis, which appears to require sustained activation of the mitogen activated protein (MAP) kinase pathway, and/or the activation of phosphotidylinositol 3-kinase (PI3 kinase). During development, a plethora of guidance factors and their receptors navigate the growing axon. However, much remained to be learned about the signaling receptors and pathways that mediate the activity of inhibitors of CNS regeneration. There is growing evidence that neuronal guidance molecules, particularly semaphorins, may also have a role as inhibitors of CNS regeneration. Although direct links have not yet been established in many cases, signals from these agents may ultimately converge upon the modulators and effectors of the Rho-family GTPases. Rho-family GTPases and their effectors modulate the activities of actin modifying molecules such as cofilin and profilin, resulting in cytoskeletal changes associated with growth cone extension or retraction.
Thompson, H. J., N. C. Tkacs, et al. (2003). "Hyperthermia following traumatic brain injury: a critical evaluation." Neurobiol Dis 12(3): 163-73.
Hyperthermia, frequently seen in patients following traumatic brain injury (TBI), may be due to posttraumatic cerebral inflammation, direct hypothalamic damage, or secondary infection resulting in fever. Regardless of the underlying cause, hyperthermia increases metabolic expenditure, glutamate release, and neutrophil activity to levels higher than those occurring in the normothermic brain-injured patient. This synergism may further compromise the injured brain, enhancing the vulnerability to secondary pathogenic events, thereby exacerbating neuronal damage. Although rigorous control of normal body temperature is the current standard of care for the brain-injured patient, patient management strategies currently available are often suboptimal and may be contraindicated. This article represents a compendium of published work regarding the state of knowledge of the relationship between hyperthermia and TBI, as well as a critical examination of current management strategies.
van Beek, J., K. Elward, et al. (2003). "Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection." Ann N Y Acad Sci 992: 56-71.
The complement system is an essential effector of the humoral and cellular immunity involved in cytolysis and immune/inflammatory responses. Complement participates in host defense against pathogens by triggering the formation of the membrane attack complex. Complement opsonins (C1q, C3b, and iC3b) interact with surface complement receptors to promote phagocytosis, whereas complement anaphylatoxins C3a and C5a initiate local inflammatory responses that ultimately contribute to the protection and healing of the host. However, activation of complement to an inappropriate extent has been proposed to promote tissue injury. There is now compelling evidence that complement activation in the brain is a double-edged sword in that it can exert beneficial or detrimental effects depending on the pathophysiological context. This review focuses on the roles of the complement system in the pathogenesis of acute brain injury (cerebral ischemia and trauma) and chronic neurodegeneration (Alzheimer's disease). Because many effects of the complement appear to promote neuronal survival and tissue remodeling, directing activation of the complement system in the brain may provide a better therapeutic rationale than inhibiting it.
Wang, H., M. Shimoji, et al. (2003). "Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson's disease." Ann N Y Acad Sci 991: 132-9.
Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD-like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP-induced neurotoxicity are not yet fully understood but involve activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage-sensing enzyme poly (ADP-ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity-induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.