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)

Parkinson's disease has been modeled in humans, lower primates, and to a lesser extent in some other vertebrates by administration of the potent neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine). The MPTP model has thus drawn considerable attention as a system to search for anti-Parkinson's disease drugs, although the cost and scarcity of primates has limited extensive applications. We now report that a parkinsonian syndrome can be elicited in the common goldfish (Carassius auratus) by a single dose of MPTP. The syndrome is characterized by profound bradykinesia (slow movement), the full extent of which is reached 3 days after MPTP administration. The reduction in movement is paralleled by loss of dopamine and norepinephrine from the forebrain and midbrain and in other brain regions as well. The toxic oxidative product of MPTP, MPP+, is also accumulated predominantly in forebrain and midbrain, and pretreatment with the monoamine oxidase blocker tranylcypromine substantially reduces accumulation of the toxic metabolite. A barely perceptible coarseness in balance adjustment also occurs in treated animals. The MPTP-treated goldfish recover normal movement and normal brain monoamine levels within 10-13 days after administration of the drug. We interpret these and other data to indicate that MPTP can induce a Parkinson's disease-like syndrome in the goldfish that is similar in many aspects to the syndrome induced by MPTP in humans and other primates. This remarkable parallel may permit the goldfish to supplement expensive and scarce primates for the purpose of searching and screening neuroprotective drugs with specific relevance to Parkinson's disease.
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PMID:A parkinsonian syndrome induced in the goldfish by the neurotoxin MPTP. 152 41

The meperidine analogue derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model of Parkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide clues to the mechanisms underlying neurodegeneration in Parkinson disease as well.
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PMID:Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 157 Mar 4

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 (PD) is a common degenerative disease, but its etiology is still unknown. However, since the discovery of MPTP, many investigators have been interested in the mitochondrial function in PD. We investigated mitochondrial functions in PD patients using the methods which have successfully been applied to mitochondrial myopathies (MM), i.e. assay of lactate and pyruvate, measurement of muscle mitochondrial respiratory enzyme activities and Southern blot analysis of muscle mitochondrial DNA. Parkinson's disease patients did not differ from controls in the mean blood and CSF (cerebrospinal fluid) lactate and pyruvate levels at the basal resting state or during an aerobic exercise. But mitochondrial complex I activity of the skeletal muscle was significantly decreased in PD. In the Southern blot analysis, we could not find major deletions or insertions of mitochondrial DNA in PD. Our studies disclosed a differential mitochondrial impairment between PD and MM. We discuss the implication of our observation.
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PMID:Is Parkinson's disease a mitochondrial disorder? 157 31

The action of toxins or the altered metabolism of dopamine may lead to oxidative stress in substantia nigra, thereby inducing dopamine cell death and the onset of Parkinson's disease. Postmortem studies showing a depletion of reduced glutathione and increased mitochondrial superoxide dismutase activity suggest the occurrence of an ongoing toxic process in substantia nigra involving free radical mechanisms. Indeed there is a selective impairment of complex I of the mitochondrial respiratory chain in substantia nigra in Parkinson's disease, mimicking the mode of action of the selective nigral toxin MPTP. The increased formation of free radical species in substantia nigra in patients with Parkinson's disease may be accelerated by an accumulation of iron within this brain region. Altered iron metabolism and impaired mitochondrial function are not apparent in the early stages of the illness and therefore may act as accelerators of some other primary pathologic process.
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PMID:What process causes nigral cell death in Parkinson's disease? 158 81

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), the active product of MPTP, caused Parkinson's disease-like symptoms. The mechanism of action of MPP+ is unknown, but analogues of MPTP lacking an N-methyl group were found to be essentially devoid of toxicity, which means that the methyl group of the pyridine ring plays a role in the toxicity. This is of interest because S-adenosylmethionine (SAM), which is the biologic methyl donor and requires a methyl group for its action, also caused MPP(+)-like motor deficits in rodents. Therefore, the requirement of a methyl group by MPTP and MPP+ for their actions suggests that, like SAM, MPP+ and MPTP may serve as methyl donors. This hypothesis was tested by reacting SAM, MPP+, or MPTP with dopamine in the presence of catechol-O-methyltransferase and measuring the methylated product of dopamine produced. Like SAM, MPP+, but not MPTP, methylated dopamine. The methylated product coeluted from chromatographic columns with standard 3-methoxytyramine. Concentrations of 15.6, 62.5, 250, and 1000 nmoles/tube increased the 3-methoxytyramine recovered above controls by 0.0, 6.88, 44.55, 129.47 and 5.8, 13.9, 50.58, 121.31 nmoles for SAM and MPP+, respectively. The dopamine that remained unreacted was dose-dependently decreased. MPTP had no significant effect. The ability of MPP+ to serve as a methyl donor may represent a mechanism for the toxicity of MPP+.
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PMID:1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) serves as methyl donor for dopamine: a possible mechanism of action. 159 Sep 12

Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery of 5 rhesus monkeys produced hemiparkinsonian syndrome in the contralateral limbs which responded to madopa or apomorphine therapy. Moreover, these two drugs induced circling away from the MPTP-treated side, amphetamine induced rotation toward the MPTP-treated side. Long-term use of madopa developed a peak-dose dyskinesia of the face and the limbs contralateral to the MPTP-treated side. The ipsilateral toxic effects were confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons of the MPTP-treated side. It is concluded that this hemiparkinsonian model of rhesus monkey will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonist induced dyskinesia in Parkinson's disease and in the search for newer methods of treatment which would produce less dyskinesia and response fluctuations.
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PMID:[Dopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated hemiparkinsonian monkeys]. 159 61

Selegiline (10 mg per day) selectively inhibits monoamine oxidase type B and thus thwarts the metabolism of dopamine by this enzyme. Selegiline has been used in the therapy of Parkinson's disease since 1986. It enhances the efficacy of levodopa, allows a reduction of the levodopa dose, and improves fluctuations in disability. It also interacts with mechanisms suspected of playing a role in the progression of the disease. Animal studies have shown that selegiline prevents the development of a Parkinson-like syndrome induced by the neurotoxin MPTP. It decreases oxidative stress resulting from the metabolism of dopamine via MAO-B. Clinical studies have shown that selegiline is effective in the therapy of untreated de novo patients: the progression of symptoms demanding the introduction of levodopa into the therapy was delayed, and the risk of needing levodopa treatment within one year was reduced by 57% with selegiline. The mode of action of this drug in the treatment of early Parkinson's disease is still under discussion. There is strong evidence that selegiline may slow the progression of the disease, but a direct symptomatic effect cannot be excluded.
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PMID:Selegiline--an overview of its role in the treatment of Parkinson's disease. 160 Mar 60

The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with idiopathic Parkinson's disease has provided new understanding into the possible mechanisms that may underlie this neurodegenerative disorder. The biochemical defect is identical to that induced in humans, primates and mice exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We have studied mitochondrial respiratory chain function in various brain regions, in skeletal muscle and in blood platelets from patients with idiopathic Parkinson's disease and from matched controls. We provide evidence suggesting that the complex I deficiency in Parkinson's disease is limited to the brain and that this defect is specific for the substantia nigra. The tissue specificity of the complex I deficiency in Parkinson's disease and its localization to the substantia nigra support the proposition that complex I deficiency may be directly involved in the cause of dopaminergic cell death in Parkinson's disease. An understanding of the molecular basis of this biochemical defect will provide valuable insight into the cause of Parkinson's disease. Our findings of normal mitochondrial function in platelet homogenates suggests that this tissue cannot be used to develop a 'diagnostic test' for Parkinson's disease.
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PMID:Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. 160 72

Although the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice have been reported to increase with age, they have not been characterized in the full spectrum of ages. Thus, in spite of a considerable body of scientific literature on the subject, previous reports leave unanswered the question of whether or not the increased susceptibility of fully mature mice is part of the aging process or simply a consequence of maturation. In the present study, the age-related effects of MPTP on striatal dopamine were studied in groups of C57BL/6 mice from young maturity to old age. The major increase in the effects of MPTP occurred between 2 and 10 months of age (equivalent to adolescence and young adulthood in humans). A slight additional increase was observed between 10 and 16 months (young adulthood and middle age) and the dopamine-depleting effects of MPTP significantly declined in truly aged animals (24 months). Of note also is the fact that normal concentrations of striatal dopamine did not decline in the later ages. Additional studies indicated that while neuronal sensitivity to the effects of 1-methyl-4-phenylpyridinium (MPP+; the putative toxic metabolite of MPTP) appears to remain constant, age-related changes in the activity of striatal monoamine oxidase type B (MAO B) paralleled the dopamine-depleting effects of MPTP in the 4 age groups. Indeed, MAO B activity increased between 2 and 16 months and declined slightly, but significantly, between 16 and 24 months. This pattern of age-related changes in MAO B, striatal dopamine and the sensitivity of the nigrostriatal system to toxic insult may provide insights into factors which have been implicated in age-related neurodegeneration and idiopathic Parkinson's disease.
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PMID:The relationships between aging, monoamine oxidase, striatal dopamine and the effects of MPTP in C57BL/6 mice: a critical reassessment. 161 16


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