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)

The evidence is compelling that free radicals, plus increases in free cytosolic Ca2+ and Na+, figure prominently in neuronal death after exposure to glutamate and dicarboxylic excitotoxins such as NMDA and kainate. However, neither the source of these radicals nor the direct connection between Ca2+ mobilization and radical production has been well defined. Electron paramagnetic resonance studies reported here indicate that intact mitochondria isolated from adult rat cerebral cortex and cerebellum generate extremely reactive hydroxyl (.OH) radicals, plus ascorbyl and other carbon-centered radicals when exposed to 2.5 microM Ca2+, 14 mM Na+, plus elevated ADP under normoxic conditions, circumstances that prevail in the cytoplasm of neurons during excitotoxin-induced neurodegeneration. In a feed-forward cycle, exposure of isolated mitochondria to .OH significantly increases subsequent radical production five- to 16-fold (average = 8.8 +/- 1.6 SE, n = 6, p > 0.01) with succinate as substrate, and also selectively impairs function of NADH-CoQ dehydrogenase activity (electron transport complex 1). These effects are also reflected by respiration rates that are reduced 48% with complex 1 substrates, but increased 27% with complex 2 substrate, after .OH exposure. Comparable complex 1 dysfunction is observed in mitochondria isolated from the substantia nigra of Parkinson's disease patients, from platelets of Huntington's disease patients, and from neocortex of Alzheimer's disease patients. Mitochondrial radical production provides a testable model, based on oxyradical toxicity, oxidative enzyme inactivation, and mitochondrial dysfunction, for the final common pathway of neuronal necrosis during excitotoxicity, and in a host of neurodegenerative disorders.
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PMID:Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implications for neurodegeneration. 803 83

The discovery of a selective striatal dopamine deficiency in Parkinson's disease has led to dopamine replacement therapies including L-DOPA, dopamine full and partial agonists, and MAO-B inhibitors. The development of new compounds and alternative methods of drug delivery may be able to overcome the long-term side effects of the established therapies. Overactivity of central glutamatergic systems appears to be important in the pathophysiology of the disorder and provides the rationale for the use of glutamate antagonists. Recent studies emphasize the significance of oxidative stress and free radical formation in the pathogenesis of Parkinson's disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of the disease. Possible neuroprotective strategies include selective MAO-B inhibitors, iron chelators, and free radical scavengers.
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PMID:Recent advances in pharmacological therapy of Parkinson's disease. 809 82

Recent experiments provide evidence that the NMDA-antagonist MK-801 has a locomotor-stimulating effect in monoamine-depleted rodents. These findings are based upon a hypothetical pathway-circuit including the basal ganglia as a model reflecting hypo- and hyperkinetic movement disorders. We have treated 5 patients suffering from Parkinson's disease with the antiepileptic drug "lamotrigine" which does not appear to be an NMDA-antagonist but acts functionally as a glutamate antagonist by inhibition of presynaptic glutamate release.
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PMID:Lamotrigine--antiparkinsonian activity by blockade of glutamate release? 809 61

Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson's disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also alters the physiological responses to dopamine receptor stimulation. Nigral lesions induce supersensitivity of D2 dopamine receptors controlling the release of glutamate and reduce the inhibitory influence of D1 receptors at postsynaptic level. These functional changes of the striatal neurons may alter the output signals from the striatum to the other structures of the basal ganglia and then produce most of the physiopathological changes observed in Parkinson's disease.
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PMID:Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson's disease. 809 20

Amantadine was introduced for the pharmacological management of neuroleptic malignant syndrome (NMS) because of its beneficial effects in Parkinson's disease which were attributed to dopaminomimetic properties. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of the glutamate receptor. Amantadine has psychotomimetic properties in patients with Parkinson's disease and normal controls. Two of four patients who received amantadine for NMS suffered an exacerbation of their psychiatric illness. Our observations support the glutamate hypothesis of schizophrenia which suggests that reduced glutamatergic transmission causes a relative dopaminergic excess in the basal ganglia and the limbic system.
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PMID:Amantadine and the glutamate hypothesis of schizophrenia. Experiences in the treatment of neuroleptic malignant syndrome. 810 Oct 93

Effects of amantadine and memantine on NMDA receptor-mediated glutamate toxicity were studied in cultured cerebellar, cortical and mesencephalic neurons. Both drugs protected cerebellar and cortical neurons against glutamate toxicity, memantine being consistently more effective than amantadine but less effective than MK-801. Glutamate toxicity of dopaminergic neurons in mesencephalic cultures was only mildly attenuated by memantine but was also only incompletely blocked by MK-801. These findings suggest that adamantanamines act by inhibiting NMDA receptor-mediated excitatory neurotransmission. However, since non-NMDA receptors appear to be principal mediators of glutamate toxicity of dopaminergic mesencephalic neurons, adamantanamines may fail to protect the nigrostriatal neurons which specifically degenerate in Parkinson's disease.
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PMID:NMDA receptor-mediated glutamate toxicity of cultured cerebellar, cortical and mesencephalic neurons: neuroprotective properties of amantadine and memantine. 810 6

Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N-methyl-D-aspartate receptor ion channel. In normal rats and monoamine-depleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK-801. When monoamine-depleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5-40 mg/kg, orally) caused a dose-dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100-200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa-carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa-carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa-carbidopa was substantially better than levodopa-carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N-methyl-D-aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.
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PMID:Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease. 791 52

Dopamine and 2-phenylethylamine levels in striatal tissue are known to be increased after administration of selegiline (L-deprenyl), but it is still difficult to explain why this treatment induces longevity or dopaminergic neuroprotection in Parkinson's disease. In the absence of significant polyamine or diamine oxidase activities in human brain, polyamines and histamine are detoxified by N-acetylation and methylation, respectively. Methylhistamine as well as N-acetylated polyamine derivatives are selective substrates for monoamine oxidase type B (MAO-B). Theoretically at least, MAO-B inhibition by selegiline could result in the increase in the levels of polyamines and their N-acetyl derivatives. This could have significance for the action of selegiline in Parkinson's disease, as overactive corticostriatal glutaminergic function has been implicated in the degeneration of nigrostriatal dopamine neurons, and polyamines are potent modulators of the excitotoxic NMDA (N-methyl-D-aspartate)-glutamate subtype receptor.
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PMID:The relevance of glial monoamine oxidase-B and polyamines to the action of selegiline in Parkinson's disease. 830 8

The clinical effects of central glutamatergic stimulation by the glycine prodrug milacemide were studied in six patients with Parkinson's disease under double-blind, placebo-controlled conditions. When administered as monotherapy at a single oral dose of 1,200 mg, the drug increased overall parkinsonian severity transiently, mostly due to an effect on rigidity. Milacemide did not, however, alter levodopa-induced dyskinesias. These results support the view that drugs acting on the glutamatergic system can influence motor function in patients with extrapyramidal movement disorders and that pharmaceutical agents that selectively block certain subtypes of glutamate receptors may ameliorate parkinsonian symptoms.
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PMID:Milacemide therapy for Parkinson's disease. 799 Aug 57

This paper reviews the changes in dopaminergic, cholinergic and glutamatergic neurotransmission, which occur in the aging of the central nervous system (CNS) and in age-related diseases: Parkinson's disease (PD) and Alzheimer's disease (AD). Dopaminergic neurotransmission is impaired with age due to degeneration of the substantia nigra pars compacta neurons and reduction of the density of postsynaptic D1 and D2 dopamine receptors in the striatum. PD is believed to be caused by a severe loss of dopaminergic neurons, which leads to nearly complete depletion of dopamine in the striatum, particularly in the putamen. The supersensitivity of postsynaptic dopamine receptors, reported by some authors, may result from compensatory mechanisms to degeneration of dopaminergic neurons. The role of aging in PD is also discussed in the paper. An interest in the role of the cholinergic and glutamatergic systems in aging results from the concept that the development of AD is due to the pathology of these systems. The data on cholinergic neurotransmission are controversial and imply that aging affects rather slightly both neurons and cholinergic receptors. In AD, however, severe degeneration of cholinergic neurons of the basal nucleus of Meynert, leading to the impairment of cholinergic neurotransmission in the hippocampus and the cerebral cortex, has been observed. In AD degeneration of glutamatergic neurons and subsensitivity of some excitatory amino acids receptors in the hippocampus and the cerebral cortex may lead to dementia. However, an increase in the glutamate release from presynaptic glutamatergic terminals may be responsible for neuronal degeneration in AD. The role of the beta-amyloid protein in a neurodegenerative activity of glutamic acid is discussed.
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PMID:Disturbances in neurotransmission processes in aging and age-related diseases. 840 65


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