Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease.
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PMID:The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates. 790 75

The serine protease inhibitor and neurite outgrowth promoter glia derived nexin (GDN) is expressed in the rat CNS during embryogenesis and persists in the olfactory system of the adult where receptor neurons are replaced throughout life. We investigated whether GDN-immunoreactivity also appears in the adult at sites of synaptic rearrangement following nerve cell death and anterograde terminal degeneration in experimental models for Parkinson's disease. Rat substantia nigra was unilaterally lesioned by stereotaxic application of different toxins: 6-hydroxydopamine, which selectively destroys dopaminergic neurons, the excitotoxic glutamate analog ibotenic acid, or the glutamate receptor agonists N-methyl-D-aspartate and quisqualate, which cause circumscript lesions of the whole substantia nigra. Nerve cell death and astroglial reactivity were monitored by parallel cresyl staining and immunocytochemistry for glial fibrillary acidic protein, at survival times ranging from 2 to 100 days. Sustained de novo synthesis of GDN occurred in the dopamine depleted caudate putamen following excitotoxin or 6-hydroxydopamine induced degeneration of the substantia nigra and of the nigrostriatal pathway provided that the lesions were nearly complete. This is consistent with compensatory changes occurring in deafferented caudate putamen and suggests a permissive role of GDN in neuronal plasticity. In the substantia nigra astroglia exhibited GDN-immunoreactivity following excitotoxin injection but not after application of 6-hydroxydopamine. Thus differences in action mechanisms of neurotoxins may have distinct consequences on the astrocyte mediated response of the same affected brain region.
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PMID:Re-expression of glia-derived nexin/protease nexin 1 depends on mode of lesion-induction or terminal degeneration: observations after excitotoxin or 6-hydroxydopamine lesions of rat substantia nigra. 790 98

Natural (GM1) and semisynthetic [113-Neu-5-AcGgOse4-2-D-erythro-1,3- dihydroxy-2-dichloroacetylamide-4-trans-octadecene (LIGA20)] glycosphingolipids, given parenterally, protect neurones against glutamate-induced death without producing the side effects typical of glutamate receptor antagonists. Chronic glutamate-related neurotoxicity (e.g., in recurring strokes in elderly hypertensive patients, and in Parkinson disease) could be prevented also by glycosphingolipids treatment, but this therapeutic intervention will require a protracted administration of orally active glycosphingolipids. Here we demonstrate that 3-6 h after oral administration of 68 mumol/kg of LIGA20 and GM1 to rats, the brain content of LIGA20 is 50-fold higher than that of GM1. The brain concentration of LIGA20 remains elevated for at least 12-24 h. Because the LIGA20 that reaches the brain is slowly metabolized, repeated oral administrations of this glycosphingolipid can yield to its accumulation in brain, and can yield various brain levels depending on the dose and frequency of drug administration. In contrast this is not possible with GM1, which given orally for 7 d, cannot accumulate in brain in pharmacologically significant concentrations.
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PMID:Brain content of glycosphingolipids after oral administration of monosialogangliosides GM1 and LIGA20 to rats. 791 19

The antispastic agent and N-methyl-D-aspartate (NMDA) receptor antagonist memantine has recently been proposed as a neuroprotective drug for use in patients with dementia syndromes with primarily temporal lobe pathology, e.g. senile dementia of Alzheimer type or dementia in Parkinson's disease. In a quantitative autoradiographic study in human post mortem hippocampus, memantine was able to inhibit binding of the noncompetitive NMDA-antagonist [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate) with inhibition constants between 3 and 10 microM, being about a factor of 10 more potent than the dissociative anaesthetic and NMDA receptor antagonist (+/-)ketamine. As these inhibition constants are well within the therapeutic concentration range of memantine, antagonism of endogenous glutamate at limbic NMDA receptors may be one molecular mechanism by which memantine is beneficial in dementia syndromes.
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PMID:Memantine inhibits [3H]MK-801 binding to human hippocampal NMDA receptors. 791 73

Somatosensory Evoked Potentials (SEPs) to median nerve stimuli were recorded in seven Cynomolgus monkeys before and after the induction of the MPTP-parkinsonian syndrome. SEPs recorded after the onset of parkinsonism showed a significant amplitude reduction of an anterior negative component peaking at about 15 ms (N15), independent of the severity of symptoms. The amplitude decrease was not reversed by the administration of I-dopa, despite clinical improvement, or cholinergic, noradrenergic and gabaergic agents. Amplitudes of N15 and of parietal P15 components were increased by the administration of the N-MDA antagonists ketamine and MK 801, and markedly increased when monkeys were given the anaesthetic agent etomidate. The present study shows that the reduced N15 SEP component of parkinsonian monkeys is similar to the reduced frontal N30 SEP component evidenced by other authors in patients affected by Parkinson's disease. The attenuation of N15 is not related to deficitary dopaminergic, noradrenergic, cholinergic and gabaergic systems. The implications of this finding and the role of glutamate toxicity are discussed.
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PMID:Effects of drug manipulations on anterior components of somatosensory evoked potentials in a parkinsonian animal model. 792 92

Using a modified open-field method, we assessed the effects of MK-801 (0.01 to 0.3 mg/kg) on locomotion and on attention to a stimulus object located in a computer-generated central zone (CZ). The CZ comprised 1/9 of the open-field floor area and was monitored independently from the rest of the area. Intermittently, a 4 x 4 x 2 cm block was placed in the CZ. In 10-min trials, non-drug tests showed that the presence of the stimulus object repeatedly and consistently increased the rats' visit duration in the CZ as compared with tests when the object was absent. Locomotor activity and entries to the CZ were unaffected by the object. MK-801 induced dose dependent hyperlocomotion and increased CZ entries and, most important, a dose dependent decrease in the animal's response to the stimulus object in the CZ. The present investigation suggests that MK-801 impacts upon two major functions; (a) a blockade of processing of attentional information from the external world and (b) activation of locomotor response systems. These findings are consistent with the hypothesis that blockade of glutamate neurotransmission by MK-801 impairs the flow of information from the external world to response mechanisms in the striatum. The present study also suggests that MK-801's potential as a therapeutic agent for motoric activation in the treatment for Parkinson's disease would be contraindicated by its disruptive influence upon attention processing functions.
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PMID:The NMDA antagonist MK-801 can impair attention to exteroceptive stimuli. 794 65

This article reviews new medical and surgical treatments for Parkinson's disease (PD). Catechol-O-methyl-transferase (COMT) inhibitors supplement the variety of antiparkinsonian drugs interacting with the dopaminergic system. Clinical studies show that COMT inhibitors prolong the action of levodopa in patients with the "wearing off" phenomenon. The atypical antipsychotic drug clozapine is the treatment of choice for the alleviation of levodopa-induced psychosis. Clozapine also has beneficial effects on tremor and levodopa-induced dyskinesias. Thus, COMT inhibitors and clozapine provide new opportunities for the treatment of patients with longstanding PD and fluctuating responses to levodopa. Experimental evidence in animals suggests that glutamate antagonists have symptomatic and neuroprotective actions in PD. At present, however, only weak antiglutamatergic drugs that have low specificity, such as memantine, amantadine, and budipine are available for clinical studies. Neurotrophic factors, in particular ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, are among the most promising new approaches for neuroprotection in PD. Problems of bioavailability, however, thus far preclude their use in patients. An improved understanding of the pathophysiology of parkinsonism has led to a renaissance of stereotaxic surgery. The subthalamic nucleus is a potential new target for surgical intervention. Ventroposterior pallidotomy has been shown to improve not only rigidity and tremor, but also akinesia. The techniques for thalamic interventions have been refined by introducing chronic thalamic stimulation. Future transplantation approaches to PD will focus on the use of genetically modified cells carrying genes for dopamine-synthesizing enzymes or neurotrophic factors. Animal studies show the feasibility of in vivo gene transfer for the treatment of PD.
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PMID:New medical and surgical treatments for Parkinson's disease. 795 44

Pharmacotherapy with levodopa for Parkinson's disease provides symptomatic benefit, but fluctuations in (or loss of) response may eventually occur. Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer side effects; novel agonists and new methods for their administration are therefore under study. Other therapeutic strategies are being explored, including the use of type B monoamine oxidase inhibitors to reduce the metabolic breakdown of dopamine, catechol-O-methyltransferase inhibitors to retard the breakdown of levodopa, norepinephrine precursors to compensate for deficiency of this neurotransmitter, glutamate antagonists to counteract the effects of the subthalamic nucleus, and various neurotrophic factors to influence dopaminergic nigrostriatal cells. Surgical procedures involving pallidotomy are sometimes helpful. Those involving cerebral transplantation of adrenal medullary or fetal mesencephalic tissue have yielded mixed results; benefits may relate to the presence of growth factors in the transplanted tissue. The transplantation of genetically engineered cell lines will probably become the optimal transplantation procedure. The cause of Parkinson's disease may relate to oxidant stress and the generation of free radicals. It is not clear whether treatment with selegiline hydrochloride (a type B monoamine oxidase inhibitor) delays the progression of Parkinson's disease, because the drug also exerts a mild symptomatic effect. Daily treatment with vitamin E (a scavenger of free radicals) does not influence disease progression, perhaps because of limited penetration into the brain.
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PMID:Treatment of Parkinson's disease. 797 71

Recent findings in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)- induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. These results suggest that the clinical trial of NMDA antagonists in patients with Parkinson's disease should be performed. Further evidence obtained in animal models of Parkinson's disease indicates that both competitive NMDA antagonists and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) antagonists show symptomatic anti-parkinsonian activity in combination with L-DOPA. Glutamate antagonists may therefore retard the progression and improve the symptomatology of Parkinson's disease. The 1-amino-adamantanes amantadine and memantine have recently been shown to be non-competitive NMDA antagonists and are widely used in Europe as anti-parkinsonian agents. Both compounds are likely to cause pharmacotoxic psychosis as an unwanted side-effect. Clinical trials are needed to test the efficacy of the 1-amino-adamantanes with respect to the progression of Parkinson's disease.
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PMID:Glutamatergic drugs in Parkinson's disease. 799 66

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15


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