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)

Common marmosets were treated daily with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 7-9 mg/kg i.p.) for 25 days, and then kept out of drug for three months before biochemical measurements in various brain areas. This treatment induced a dramatic fall (-80%) in dopamine, homovanillic acid and dihydroxyphenylacetic acid levels in the putamen and caudate nucleus, and a significant but less pronounced reduction (less than or equal to 50%) in the levels of these compounds in the nucleus accumbens. In contrast, the concentrations of four neuropeptides: met-enkephalin, leu-enkephalin, substance P, and cholecystokinin, remained unaltered in all brain areas examined in MPTP-treated marmosets. Therefore the neuropeptide alterations previously reported in Parkinson's disease are probably not secondary to the severe lesion of dopaminergic neurones, but constitute another intrinsic feature of the disease.
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PMID:Levels of Met-enkephalin, Leu-enkephalin, substance P and cholecystokinin in the brain of the common marmoset following long term 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine treatment. 246 6

Six young adult marmosets received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in multiple doses (total 8-16 mg/kg over 2-13 days) sufficient to produce a parkinsonian syndrome and were killed up to 3.5 months later. Cellular changes were found in the substantia nigra, ventral tegmental area, and hypothalamus. The earliest histological abnormalities were axonal swellings in proximal parts of nigrostriatal axons. Subsequent changes in the substantia nigra were reduced Nissl staining, reduced cell volume, and aggregation and loss of melanin granules. Other effects were reduced nuclear and nucleolar volumes, depletion of cells, and hyperplasia of glial cells. Shrunken cytoplasm and nuclei stained uniformly with eosin, and no cells showed cytoplasmic swellings or inclusions. These cellular alterations, with nuclear changes resembling karyolysis, do not occur in Parkinson's disease, which is characterised by Lewy body inclusions and signs of chromatolysis. The rapid appearance of axonal swellings, disruption of Nissl substance, and cell shrinkage suggest an insult to energy producing mechanisms. In this study, the absence of histological evidence of toxicity in the locus coeruleus and also in the substantia innominata and in serotonergic cell groups is unlike the more widespread degenerative changes of Parkinson's disease.
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PMID:The evolution and distribution of morphological changes in the nervous system of the common marmoset following the acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 249 38

The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that produces the symptoms of Parkinson's disease, can be fully prevented in experimental animals by inhibiting monoamine oxidase B. On the basis of this observation, a double-blind, placebo-controlled study in patients with early Parkinson's disease was initiated to determine whether deprenyl (a selective monoamine oxidase B inhibitor) would delay the need for L-dopa therapy by slowing the progression of the disease. Fifty-four patients were randomly assigned to deprenyl (10 mg/day) or placebo treatment groups and followed until L-dopa therapy was indicated or until the patient had been in the study for 3 years. Analysis of Kaplan-Meier survival curves for each group showed that deprenyl delayed the need for L-dopa therapy; the average time until L-dopa was needed was 312.1 days for patients in the placebo group and 548.9 days for patients in the deprenyl group. Disease progression, as monitored by five different assessment scales, was slowed (by 40 to 83% per year) in the deprenyl group compared to placebo. Therefore, early deprenyl therapy delays the requirement for antiparkinsonian medication, possibly by slowing progression of the disease.
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PMID:The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. 211 91

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in 1983 as a parkinsonian neurotoxin, endogenous or exogenous MPTP-like substances have been extensively investigated. Tetrahydroisoquinoline (TIQ) is a trace amine newly discovered in parkinsonian and control human brains. Like MPTP, TIQ inhibits tyrosine hydroxylase and NADPH ubiquinone oxidoreductase to reduce dopamine and ATP in the nigrostriatal dopaminergic neurons. TIQ produced parkinsonian symptoms after chronic administration in monkeys, which were recovered by L-DOPA. However, TIQ does not cause neuronal cell death at least in young monkeys. If some MPTP-like neurotoxins could be the cause of Parkinson's disease, some other factors such as immunological, neurotrophic, or genetic factors may work together with the putative neurotoxins during the process of aging.
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PMID:[The search for endogenous or exogenous MPTP-like substances]. 251 47

Previous parkinsonian rat models have generally been characterized by unilateral destruction of both the nigrostriatal pathway and the mesolimbic pathway using the neurotoxin 6-hydroxydopamine (6-OHDA). We created a hemiparkinsonian model in which there is 6-OHDA-induced destruction of the dopaminergic nigrostriatal pathway but sparing of the dopaminergic mesolimbic pathway. This resulted in reproducible, quantifiable rotational behavior in response to either amphetamine or apomorphine and a near total depletion of dopamine in the striatum ipsilateral to the lesion with a dorsolateral distribution of supersensitive dopaminergic D2 receptors. This model parallels the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced hemiparkinsonian model in primates and more closely approximates the extent of neurodegeneration seen in human idiopathic Parkinson's disease than previous parkinsonian rat models. It may therefore prove a convenient model for studying the recently reported phenomenon of sprouting from host dopaminergic neurons following tissue implantation.
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PMID:A 6-hydroxydopamine-induced selective parkinsonian rat model. 252 89

It is known that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces Parkinson's-like disease in primates and humans, depletes hepatocytes of ATP and subsequently causes cell death. Incubation of rat liver mitochondria with MPTP and 1-methyl-4-phenyl pyridinium ion (MPP+) significantly inhibited incorporation of 32Pi into ATP.MPTP and MPP+ inhibited the development of membrane potential and pH gradient in energized rat liver mitochondria, suggesting that reduction of the proton motive force may have reduced ATP synthesis. Since deprenyl, an inhibitor of monoamine oxidase, prevented the formation of MPP+ and inhibited the decrease in membrane potential caused by MPTP, but not that caused by MPP+, these effects of MPTP, as well as cell death, probably were mediated by MPP+. This mechanism may play a role in the specific loss of dopaminergic neurons resulting in MPTP-induced Parkinson's disease.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine inhibits proton motive force in energized liver mitochondria. 254 Jul 15

Idiopathic Parkinson's disease may have a low-level familial association but does not follow mendelian patterns of inheritance. Since inheritance of some components of the electron transport chain is nonmendelian and since inhibition of the electron transport chain with the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models Parkinson's disease in humans and animals, we evaluated catalytic activities of the electron transport chain in platelet mitochondria purified from patients with idiopathic Parkinson's disease. All 10 patients studied had significant reductions of complex I (NADH:ubiquinone oxidoreductase) activity. Succinate:cytochrome c oxidoreductase activity was less strikingly reduced. We hypothesize that the complex I abnormality may have an etiological role in the pathogenesis of Parkinson's disease and that this defect may be derived via the mitochondrial genome.
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PMID:Abnormalities of the electron transport chain in idiopathic Parkinson's disease. 255 92

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome that resembles Parkinson's disease. To compare the biochemical abnormalities produced by this compound in human beings with those occurring in Parkinson's disease, we examined biogenic amine metabolites in cerebrospinal fluid and urine from six patients with MPTP-induced parkinsonism and eight patients with Parkinson's disease. In both forms of parkinsonism, the cerebrospinal fluid levels of homovanillic acid, the major metabolite of dopamine, were reduced, whereas the levels of the serotonin metabolite 5-hydroxyindoleacetic acid were normal. The cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine in the brain, after adjustment for plasma MHPG, were elevated (greater than 6.0 ng per milliliter) in MPTP-induced parkinsonism, whereas MHPG levels were reduced (less than 6.0) in Parkinson's disease. Neurons containing norepinephrine in the brain are involved in the degenerative process of Parkinson's disease, whereas they are spared in MPTP-induced parkinsonism. The selective destruction by MPTP of nigrostriatal dopamine neurons that is responsible for the movement disorder also appears to result in an increase in central noradrenergic activity, which is not possible in Parkinson's disease. Thus, differences in central noradrenergic activity, reflected in cerebrospinal fluid levels of MHPG, distinguish these two forms of parkinsonism.
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PMID:The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 258 Nov 35

Administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes behaviors reminiscent of idiopathic Parkinson's disease in man and other primates, but development of such symptomology has not been reported to date in other species. We now report a sheep model which responds to administration of low levels of the compound with well defined, apparently permanent symptomology very similar to that seen in primates. Histological examination indicates drug dependent destruction of the substantia nigra which, in sheep, lacks the high levels of neuromelanin present in primates. Following infusion of either MPTP or MPP+, only the metabolite MPP+ was detected in serum with this metabolite demonstrating a very long half life. The rapid disappearance of MPTP suggests that its potency will be directly related to a function of body size and inversely related to heart rate.
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PMID:A sheep model for MPTP induced Parkinson-like symptoms. 258 22

The 2-deoxyglucose metabolic mapping technique has been used to investigate the neural mechanisms which underlie the symptoms of Parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease. In six cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was either (a) administered intravenously to induce generalized Parkinsonism, or (b) infused into one carotid artery to induce unilateral Parkinsonism. Post-mortem examination revealed profound cell loss from the substantia nigra, pars compacta either bilaterally or unilaterally in the two groups, respectively. In addition, there was pathological involvement of the ventral tegmental area and locus coeruleus in animals receiving intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2-Deoxyglucose autoradiography revealed widespread changes in 2-deoxyglucose uptake in the brains of parkinsonian animals when compared to controls. Most of these changes were in basal ganglia and related structures and were qualitatively similar in the two groups of experimental animals. Prominent increases in 2-deoxyglucose uptake were observed in the lateral segment of the globus pallidus (24-27%), the ventral anterior and ventral lateral nuclei of the thalamus (14-22%) and the nucleus tegmenti pedunculopontinus of the caudal midbrain (17-69%). A profound decrease (17-26%) in 2-deoxyglucose uptake was observed in the subthalamic nucleus. We propose these data to indicate that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism there is the following pattern of abnormal neuronal activity in basal ganglia circuitry: (i) increased activity in the projection from the putamen to the lateral segment of the globus pallidus; (ii) decreased activity in the projection from the putamen to the medial segment of the globus pallidus; (iii) decreased activity in the projection from the lateral segment of the globus pallidus to the subthalamic nucleus; (iv) increased activity in the projection from the subthalamic nucleus to the globus pallidus; and (v) increased activity in neurons of the medial segment of the globus pallidus projecting to the ventral anterior/ventral lateral thalamus and the pedunculopontine nucleus. These results are compared to the 2-deoxyglucose uptake findings in previous studies from this laboratory in hemiballism and hemichorea in the monkey. The central importance of the subthalamic nucleus in all three conditions is proposed, and supportive evidence for the excitatory nature of subthalamic efferent fibres is adduced.
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PMID:Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 258 50


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