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)

Disorders of the basal ganglia and the extrapyramidal motor system exhibit an imbalance of neurotransmitter concentrations in affected neurons. For three synapses with dopamine, acetylcholine, and gamma-amino butyric acid (GABA), mathematical models of synaptic transmission are developed. To describe the kinetics of transmitter substances, compartment analysis is used. Membrane potential behaviour is described by the Hodgkin-Huxley equations with an additional equation accounting for a presynaptic calcium current mediating transmitter release. At the postsynaptic site, activated receptor molecules control the activity of ion channels, eliciting either inhibitory or excitatory postsynaptic potentials. A simple model of the feedback loop connecting the caudate nucleus and the substantia nigra is simulated on a digital computer using the simulation language ACSL. A comparison of the control case with a model of Parkinson's disease shows a shift of eigenvalues towards zero in the diseased state.
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PMID:A computer model of neuronal pathways in the basal ganglia. 301 86

The nigrostriatal neurotoxin N-methyl-1,2,3,6-tetrahydropyridine (MPTP) causes Parkinsonism in humans and laboratory animals. MPTP neurotoxicity is dependent on its oxidation to N-methyl-4-phenylpyridine (MPP+). The mechanism by which MPP+ causes destruction of dopamine-containing nigrostriatal cells is unknown. Here we show that MPP+ but not MPTP is taken up by energized mitochondria. MPP+ in the presence of dopamine and particularly of 6-hydroxydopamine stimulates Ca2+ release from mitochondria. Ca2+ release is accompanied by hydrolysis of intramitochondrial pyridine nucleotides. Our findings suggest that the MPTP-induced model of Parkinson's disease may be due to a disturbed Ca2+ homeostasis in dopamine neurons.
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PMID:N-methyl-4-phenylpyridine (MMP+) together with 6-hydroxydopamine or dopamine stimulates Ca2+ release from mitochondria. 308 73

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans and other primates. It is less specific and much less potent in mice and has only slight effects in rats. Differences in rates and sites of metabolism of MPTP to its active, toxic, highly polar metabolite, MPP+ (1-methyl-4-phenylpyridine), appear to influence species specificity. In rats, type B monoamine oxidase (MAO-B), which mediates the conversion of MPTP to MPP+, may act as an enzymatic barrier at brain microvessels, whereas in primates the enzyme, present mainly in astrocytes, appears important for bioactivation of MPTP into the toxic metabolite. MPP+ is a substrate for catecholamine uptake sites and is concentrated in these neurons. The molecular mechanism of MPP+ toxicity has not been established definitively, but conversion to a free radical or uptake by mitochondria and inhibition of mitochondrial respiratory enzymes, leading to calcium release and cell death have been suggested. The discovery of toxin which causes an animal model of Parkinson's disease has stimulated new research on environmental factors that might contribute to this progressive degenerative disorder and provides a means for assessing new approaches to therapy.
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PMID:MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease. 331 63

Biochemical markers for serotoninergic and catecholaminergic neurons in frontal and temporal poles were examined post mortem in brains of patients with Alzheimer's disease, Parkinson's disease, and the two combined. Binding of [3H] citalopram to serotoninergic uptake sites and levels of serotonin were decreased by 40 to 50% in brains of persons in each disease category. In contrast, significant reductions of catecholaminergic markers were not detected. In all three disease groups, the choline acetyltransferase activity was reduced by 50 to 60%. Binding sites for adenosine (A1), muscarinic cholinergic, phencyclidine, beta-adrenergic, and calcium antagonist receptors were unchanged. We conclude that substantial damage to serotoninergic neurons occurs in persons with Parkinson's and Alzheimer's diseases.
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PMID:Aminergic systems in Alzheimer's disease and Parkinson's disease. 347 96

In mice, chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an increase in the maximum number of [3H]spiperone binding sites in the striatum. The sensitivity of striatal protein phosphorylation to calcium plus calmodulin is also potentiated in MPTP-treated mice. These observations are associated with an enhancement of apomorphine-induced climbing behavior in the drug-treated animals. The results of this study suggest that in an animal model for Parkinson's disease, MPTP interrupts the dopamine (DA) transmission by chemically denervating the nigrostriatal neurons and through a compensatory mechanism, it increases the number of DA receptors as well as the sensitivity of protein phosphorylation to calcium plus calmodulin in mouse striatum. The latter two events may contribute to the development of DA receptor supersensitivity.
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PMID:Pharmacological effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine receptor system. 348 26

To our knowledge, this is the first case report of a multiple, low dosage ingestion of manganese. A 66-year-old male patient is presented, who ingested 125 ml of a 8% solution of potassium permanganate (10 g) within 4 weeks. As early as 2 weeks after the beginning of poisoning, psychological alterations were noted. Neurological examination revealed disturbances of many subsystems of the CNS. Visually evoked potentials showed prolongation of the P2-latency, not reported in earlier publications. Levels for manganese were elevated in peripheral blood as well as in hair samples. Treatment with calcium trisodium pentetate decreased serum levels and increased urine excretion of manganese. Nine months after poisoning, the first signs of progressive Parkinson disease became evident. The time-course of neurological symptoms seems to depend on a critical dose of manganese.
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PMID:Chronic enteral poisoning caused by potassium permanganate: a case report. 372 48

The calcium-channel ligand, nimodipine (Bay e 9736), in submicromolar concentrations (10(-7) to 10(-5) M), enhanced the potassium (25 mM) or electrical stimulation (1 Hz, 1 ms, 180 pulses) evoked release or [3H]dopamine from rat striatal slices, while it inhibited the release of [3H]acetylcholine. Nimodipine had similar effects on slices from the cerebral cortex loaded with [3H]dopamine or [3H]acetylcholine, the electrical stimulation evoked release of the catecholamine was enhanced, while release of [3H]acetylcholine was suppressed. The data indicate that nimodipine may distinguish between Ca2+ channels in dopaminergic and cholinergic nerve-terminals. The simultaneous elevation of dopamine release and suppression of acetylcholine release may prove useful in the treatment of Parkinson's disease.
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PMID:Dopamine release is enhanced while acetylcholine release is inhibited by nimodipine (Bay e 9736). 395 99

Two possible interpretations of the origin of Lewy bodies and adrenal bodies found in Parkinson's disease are now under discussion: a disorder of (1) catecholamine metabolism or (2) sphingomyelin lipidosis. From the electron probe microanalysis of Lewy bodies and adrenal bodies, we find that the Lewy body contains sulfur, calcium, and phosphorus, and the adrenal body also contains these three elements. Furthermore, a positive correlation was obtained between the X-ray intensity of the sulfur and the diameter of adrenal body. For Lewy bodies, this correlation was not obtained. The results suggest that a common mechanism may exist for the production of Lewy and adrenal bodies, although they differ somewhat in their accumulation of sulfur. It is considered that both structures may originate, in part, from degenerated protein containing sulfur.
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PMID:Element analysis of Lewy and adrenal bodies in Parkinson's disease by electron probe microanalysis. 684 84

We describe a clinical picture identical to Parkinson disease complicating postoperative hypoparathyroidism. Unlike most previously described cases, the extrapyramidal disorder was reversed completely by repletion of serum calcium.
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PMID:Reversible Parkinson syndrome complicating postoperative hypoparathyroidism. 719 11

This review describes recent advances in our understanding of the pharmacology of excitatory amino acid receptors, and the application of this knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid receptors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have shown there to be a large number of potential subtypes of receptors in both these families. Antagonists have been developed for the NMDA receptor which can interact with at least four independent drug recognition sites on the receptor. For the AMPA/kainate receptor, two classes of antagonist have so far been identified. Reasonably potent, selective and brain-penetrating antagonists now exist for virtually all these sites, and compounds inhibiting the release of glutamic acid presynaptically have also been identified, such as riluzole. The ability of glutamic acid to kill neurons (excitotoxicity) seems to be mediated, in most cases, by an interaction with NMDA receptors, leading to an uncontrollable rise in intracellular calcium concentrations and thence cell lysis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenerative foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate receptor antagonists have neuroprotective effects. Clinical trials are underway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encephalopathy. Ingestion of excitatory amino acids may play a role in neurological conditions of dietary aetiology, such as neurolathyrism and domoic acid intoxication. For chronic neurodegenerative diseases, the role of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic lateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, but the relevance of these animal models to the human pathology is not clear. However, preliminary clinical results suggest riluzole to be efficacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treatment of Parkinson's disease. The next few years could witness a breakthrough in the treatment of neurological conditions as drugs that interfere with glutamatergic transmission become available for clinical use.
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PMID:Excitatory amino acid receptors and neurodegeneration. 748 87


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