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)

Administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to primates produces an excellent behavioral model of idiopathic Parkinson's disease. In the vervet monkey, regional biochemical differences in the striatum of two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated groups were examined one to two months after treatment and compared with controls; one group displayed no observable gross motor abnormalities after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (asymptomatic), whereas the other group became markedly parkinsonian (symptomatic). In both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated groups massive depletions of dopamine and homovanillic acid concentrations were observed in the striatum; generally, dopamine losses in the symptomatic group (greater than 95%) were greater than in the asymptomatic group (greater than 75%). However, in striatum, a marked heterogeneity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine susceptibility was found; certain striatal regions having 99% depletion of dopamine even in asymptomatic monkeys. Overall, in ventromedial regions of striatum the losses of dopamine and homovanillic acid concentrations were less than in dorsolateral regions at the same coronal level. There was a significant negative correlation between control homovanillic acid/dopamine ratios and susceptibility of examined regions to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Unlike idiopathic, but similar to postencephalitic, Parkinson's disease, dopamine and homovanillic acid levels in caudate nucleus were not spared relative to putamen; in fact, in the asymptomatic group caudate nucleus dopamine and homovanillic acid concentrations were depleted to a greater extent than in putamen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Symptomatic and asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates: biochemical changes in striatal regions. 262 29

Eight ewes, divided into two groups based on age, with group 1 7-8 and group 2 1-3 years old, respectively, were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously (IV) at cumulative doses of 2.0 to 34.6 mg/kg body weight. Two group 1 sheep, given cumulative doses of 2 and 8.5 mg/kg, developed persistent severe neurologic signs of body stiffness and rigidity, paucity of movement, intention body tremors, and abnormal body posture and stance similar to those signs in MPTP-induced disease in people and primates. After their acute onset, these persistent signs were nonprogressive up to the observation period of 32 days post infusion. None of the younger ewes had persistent neurologic symptoms at equivalent cumulative doses (9.0 mg/kg). The only pathologic changes were microscopic lesions in the central nervous system, consisting of bilaterally symmetrical neuronal chromatolysis and necrosis limited to the substantia nigra and locus ceruleus. These lesions were found in two persistently affected and two younger sheep, suggesting age-based differences in dose response and the threshold of clinical expression of disease. Serum MPTP half-life was 11 days. Thus sheep exposed to MPTP could be an alternative model to the primate for the comparative study of clinical, pathologic, and biochemical mechanisms in MPTP neurotoxicity and Parkinson's disease in people.
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PMID:MPTP-induced Parkinson-like disease in sheep: clinical and pathologic findings. 263 35

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

Great interest has been recently raised by the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a meperidine analogue capable of producing an irreversible Parkinson's disease. On the basis of papers published during the last years, we examined the structural features and the specific mechanism of action of this substance at the level of dopaminergic neurons. Furthermore, the clinical features of the experimental Parkinson model, obtained by means of MPTP inoculation in various animals and their similarities to the analogous human disease are described. We can conclude that the MPTP discovery enhances the hypothesis that Parkinson's disease can be also attributed to toxic factors.
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PMID:[MPTP: a new chapter in the history of Parkinson's disease]. 268 42

It is now well recognized that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce a syndrome in human and non-human primates similar to Parkinson's disease. This highly selective neurotoxin, which affects specific catecholaminergic nuclei in the brainstem, has provided an important new tool for the study of Parkinson's disease. In this article we review several specific areas related to current research on MPTP, including the question of disease progression, issues regarding the validity of the animal model induced by MPTP, the role of aging in regard to its neurotoxicity and Parkinson's disease, and new therapeutic strategies that have evolved from basic research with the compound. We conclude that both clinical and basic research stemming from the discovery of MPTP have provided valuable insights regarding both the cause and treatment of Parkinson's disease.
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PMID:MPTP-induced parkinsonism as a model for Parkinson's disease. 269 34

Progress in the research on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is reviewed, and the impact given by MPTP to the studies on Parkinson's disease is discussed. Our data on the mechanism of the neuronal degeneration in MPTP-induced experimental parkinsonism are also presented. We studied the effects of the 1-methyl-4-phenylpyridinium ion (MPP+) on mitochondrial respiration. Mitochondria were prepared from mouse brains, and oxygen consumption was measured polarographically. Activity of Complex I was measured after the incubation of the mitochondria with NAD(+)-utilizing substrates in the TCA cycle and ADP. MPP+ significantly inhibited the state 3 respiration supported by glutamate. Amount of ATP synthesized was also significantly reduced by MPP+. Activity of Complex I was significantly inhibited by MPP+. This inhibition was observed with 0.05 mM of MPP+ when intact mitochondria were used. These observations suggest mitochondria as the most probable site of the action for MPP+. It appears to be important to search for endogenous or exogenous toxic substances with similar pharmacological properties as MPTP to elucidate pathogenesis of Parkinson's disease. In addition, studies on mitochondrial functions in Parkinson's disease seem to be also important. Some preliminary data are shown.
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PMID:[Contribution of MPTP to studies on the pathogenesis of Parkinson's disease]. 269 96

The tetrahydro-beta-carboline derived from the condensation of N-methyltryptamine and formaldehyde, a semirigid tricyclic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tha has been detected in the brains of normal laboratory rats, is biotransformed in a monoamine oxidase B (MAO-B) catalyzed reaction to the corresponding dihydro compound at a rate that is approximately 0.5% of that observed with MPTP. The corresponding tetrahydroindenopyridine in which the double bond beta,gamma to the nitrogen atom retains allylic character is a somewhat better MAO-B substrate. The steric bulk of the nitrogen and methylene bridges in addition to ring strain present in the proposed carbon-centered radical intermediates derived from these types of tricyclic structures may contribute to their relatively poor MAO-B substrate properties. Although no MPTP-like neurotoxic properties were observed following acute administration of the test compounds to mice, we speculate that the chronic accumulation of beta-carbolinium type metabolites could contribute to the rate of nigrostriatal cell loss associated with idiopathic Parkinson's disease.
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PMID:Studies on semirigid tricyclic analogues of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 278 13

Idiopathic Parkinson's disease has been postulated to result from exposure to environmental toxins similar to the parkinsonism-causing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This study examines the interactions of MPTP with the cytochrome P-450 system--an enzyme system which is known to be involved in the detoxication of MPTP. In vitro studies, using control hepatic microsomes, studied changes in cytochrome P-450 content and enzyme activity with varying concentrations of MPTP and substrates. In vivo liver and brain studies were conducted using groups of 4 animals treated intraperitoneally with varying doses of MPTP and sacrificed at varying time intervals after treatment. Changes in cytochrome P-450 enzyme contents and activities were determined using standard analytical procedures. MPTP was found from in vitro studies to cause a mixed non-competitive inhibition of cytochrome P-450 dependent ethoxyresorufin O-dealkylase activity with an inhibition constant (Ki) of 0.06 mM. Two binding sites of MPTP to hepatic cytochrome P-450 were found by spectral perturbation studies--the higher affinity site binding about a hundred times more avidly to MPTP than the other. In vivo studies showed a depression of cytochrome P-450 content and activity in a dose-dependent manner. Cytochrome P-450 levels were lowest 3 to 6 hours after treatment with MPTP. MPTP was also found to cause a dose-dependent decrease in the cytochrome P-450 enzyme activities bufuralol hydroxylase (buf) and aryl hydrocarbon hydroxylase (AHH) in the brain. Bufuralol hydroxylase activity was found to be about 2000 times more sensitive than aryl hydrocarbon hydroxylase to the effects of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies on the interactions of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with the cytochrome P-450 enzyme system--clues to a possible aetiological factor in Parkinson's disease. 278 64

Chronic exposure to manganese-laden dusts induces, in humans and lower primates, neurological disorders with clinicopathological features that resemble idiopathic Parkinson's disease. As many authors have suggested, manganese neurotoxicity could be related to the capability of this metal to increase catechol autoxidation in catecholaminergic neurons, therefore increasing the formation of toxic compounds such as peroxides, superoxides, free radicals, and semi-orthoquinones. Oxidative stresses and consequent neuronal damage could then occur if physiological scavenger mechanisms fail in their detoxifying action. We here report that manganese chloride weakly inhibits, in a dose-dependent way by a reversible competitive mechanism, human brain glutathione-S-transferases possibly suggesting that manganese intoxication could cause intraneuronal accumulation of cytotoxic compounds. We also report that both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin known to induce in man Parkinson-like syndromes, and one of its metabolites 1-methyl-4-phenylpyridinium failed to decrease glutathione-S-transferase activity.
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PMID:Interactions of manganese with human brain glutathione-S-transferase. 278 43

The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depletes forebrain dopamine is not fully understood, but a necessary step involves the formation of neurotoxic MPP+ by monoamine oxidase type B (MAO-B). The histamine neurons in the brain contain MAO-B and are a possible site for the production of MPP+. Two weeks after MPTP injections (2 X 50 mg/kg i.p.) in C-57 mice, striatal dopamine was reduced by more than 70%. However, histamine levels in neocortex, hippocampus and hypothalamus were unaffected by this neurotoxic dose of MPTP. Thus, as in Parkinson's disease, central histaminergic systems appear to be spared in the MPTP model.
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PMID:Cerebral histamine levels are unaffected by MPTP administration in the mouse. 279 95


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