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

Immunoassays sensitive to a broad range of compounds structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) and 1-methyl-4-phenylpyridine (MPP+) have been developed and used to test for the presence of possible chemically related neurotoxins in the brains of Parkinson's disease patients. The sensitivity and chemical reactivity of the polyclonal antibodies used in these assays have been characterized with a range of endogenous and chemically related materials. Two methods were developed and tested for extraction followed by chromatographic separation which would be applicable to stored or accumulated substances. The immunoassays were tested and applied to the assay of tissue extracts from MPTP or MPTP-analogue exposed animals, and indicated detectability of MPP(+)-immunoreactivity greater than 8 weeks after exposure to MPTP in monkey brain. No difference in immunoactivity was measured in extracts from human brains of Parkinson's disease patients or controls, and particularly low levels of immunoreactivity were found in the striatum relative to the levels measured in several cortical regions. From these studies, there is no evidence for the role of an environmental neurotoxin chemically related to MPTP in the pathogenesis of Parkinson's disease.
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PMID:Search for neurotoxins structurally related to 1-methyl-4-phenylpyridine (MPP+) in the pathogenesis of Parkinson's disease. 157 86

Parkinson's disease is one of the commonest neurodegenerative disorders in Western society. Although the neuropathological changes have been well documented, the underlying biochemical defect is unknown. Toxins may play a part in the aetiology of this disorder. It has been shown that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a Parkinson-like syndrome in both man and primates and 1-methyl-4-phenylpyridine (MPP+), a metabolite of MPTP, inhibits NADH-ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain. We studied mitochondrial respiratory chain function in skeletal muscle from patients with Parkinson's disease because, like brain, it has a high dependence on oxidative metabolism. Our results show low activity in all complexes studied (I, II and IV). The implications of these findings are discussed in relation to the aetiology of Parkinson's disease.
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PMID:Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. 165 41

Exposure of drug addicts to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has caused a Parkinsonian syndrome accompanied by a selective destruction of dopamine containing neurones in the pars compacta of the substantia nigra. MPTP in the human causes a severe irreversible state that very closely resembles idiopathic Parkinson's disease both in its clinical features and response to pharmacological treatment. Interest in potential environmental agents that might play a role in the aetiology of idiopathic Parkinson's disease is likely to increase as the result of the discovery of the relatively simple molecule MPTP which is highly toxic to the substantia nigra. Until the discovery of the neurotoxicity of MPTP there was no effective animal model of Parkinson's disease. Administration of PTP to monkeys induces persistent parkinsonism which responds to classical antiparkinsonian therapy. The morphological and biochemical changes in the brains of the animals are more limited and selective than those seen in idiopathic Parkinson's disease. The model of MPTP-treated monkeys appears to provide a useful testbed for the evaluation of future treatments for the disease. The precise mechanism of MPTP toxicity has yet to be determined and may provide the clue to the mechanism of neuronal death in Parkinson's disease. After entering the brain MPTP is oxidized to MPP+ (1-methyl-4-phenylpyridine) at an extraneuronal site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Significance of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for the etiology and therapy of idiopathic Parkinson disease]. 265 47

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine, which has a high affinity for melanins. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.
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PMID:Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. 288 68

Paraquat structurally resembles N-methyl-4-phenyltetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridine (MPP+). MPTP and MPP+ are neurotoxic chemicals, which induce in exposed humans and in animal-models a Parkinson's disease. A high correlation between the incidence of Parkinson's disease and herbicide use in Canada led to the assumption that paraquat could give rise to parkinsonism. We have therefore carried out a follow-up study with patients having had dermal contact with paraquat or having swallowed paraquat accidentally or in a suicidal attempt. 7 patients took part in the study. Three of them had dermal contact. One had ingested paraquat by accident and three were survivors from suicidal paraquat intake. It was possible to exclude parkinsonism in all patients. One patient exhibited tardive dykinesia most likely due to a long term therapy with neuroleptic drugs.
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PMID:[No Parkinsonian syndrome following acute paraquat poisoning]. 290 65

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

C57 black mice were injected repeatedly with maximal tolerated doses of 2 chemical analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 4-phenylpyridine and 4-phenyl-1,2,3,6-tetrahydropyridine. Although both compounds were clearly acutely toxic to mice, neither caused any reduction in striatal dopamine content after chronic exposure. Two MPTP analogues which may be formed endogenously during the metabolism of brain monoamines, 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydro-beta-carboline, were injected repeatedly into common marmosets. Again, although both compounds appeared highly toxic, neither caused any reduction in striatal dopamine content. It appears unlikely that any of these 4 MPTP analogues causes idiopathic Parkinson's disease.
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PMID:4-phenylpyridine and three other analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lack dopaminergic nigrostriatal neurotoxicity in mice and marmosets. 310 59

The herbicide paraquat has been suggested as a causative agent for Parkinson's disease because of its structural similarity to a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which may induce a parkinsonism-like condition. MPTP as well as its metabolite 1-methyl-4-phenylpyridine have melanin affinity, and the parkinsonism-inducing potency of MPTP is much stronger in species with melanin in the nerve cells. Autoradiography of [3H]MPTP in experimental animals has shown accumulation in melanin-containing tissues, including pigmented neurons. In the present whole body autoradiographic study accumulation and retention was seen in neuromelanin in frogs after i.p. injection of [14C]paraquat or [14C]diquat. By means of whole body autoradiography of [14C]diquat in mice (a species with no or very limited amounts of neuromelanin) a low, relatively uniformly distributed level of radioactivity was observed in brain tissue. Accumulation of toxic chemical compounds, such as paraquat, in neuromelanin may ultimately cause lesions in the pigmented nerve cells, leading to Parkinson's disease.
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PMID:Autoradiography of [14C]paraquat or [14C]diquat in frogs and mice: accumulation in neuromelanin. 326 93

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

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is toxic to the nigrostriatal dopaminergic neurons and produces a syndrome similar to Parkinson's disease. Conversion of MPTP to 1-methyl-4-phenylpyridine (MPP+) by monoamine oxidase-B (MAO-B) appears necessary for this neurotoxicity. When MPTP was used as the substrate for the histochemical localization of monoamine oxidase activity on sections of the rat brain, only a few specific sites were found in which MPTP oxidation to MPP+ occurs. These include the noradrenergic and serotoninergic neurons of the brainstem and the histamine neurons of the caudal hypothalamus. Dopamine neurons themselves do not display the capacity to oxidize MPTP. It is proposed that the conversion of MPTP to MPP+ occurs via MAO-B within serotonin and histamine neurons which may innervate the substantia nigra where the toxin MPP+ could be released and then taken up into the dopamine neurons.
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PMID:Histochemistry of MPTP oxidation in the rat brain: sites of synthesis of the parkinsonism-inducing toxin MPP+. 348 52


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