Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:28289-54-5 (MPTP)
 5,211 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between structural specificity of the main stages of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action and the display of parkinsonogenic properties among homologous structures in a number of 4-tolyl derivatives of MPTP has been studied. All the compounds are better substrates for monoamine oxidase (MAO) than MPTP. MAO is inactivated during the reaction according to a mechanism of irreversible inhibition by 2,3-dihydropyridinium metabolite. All the tolyl derivatives are stronger inhibitors of MAO than 1-methyl-2,3-dihydropyridinium (MPDP). A significant contribution of enzyme inhibition to the catalytic conversion of the substrate leads to the fact that substrates having equal (para isomer) or even higher (meta isomer) values of catalytic parameters are oxidized by MAO to a lesser extent than MPTP. It has been found that all 4-arylpyridiniums (final products of MATP bioconversion) competitively and reversibly inhibit [14C]dopamine (DA) uptake in mouse brain synaptosomes. Affinity toward DA transporter characterized by KI (microM) is 0.37 +/- 0.04, 0.7 +/- 0.1, 2.0 +/- 0.15, 2.0 +/- 0.35 for MPP, and its o-, m-, and p-tolyl derivatives, respectively. Joint calculation of specificity factors for the processes discussed define the following rank order for the bio-delivery of MATP's metabolic produces into DA nerve terminals: o-tolyl > MPTP >> m-tolyl > p-tolyl. The regularity revealed is in good agreement with the observed relative potency of these compounds to cause dopaminergic neurodegeneration.
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PMID:Molecular basis of discrepancies in neurotoxic properties among 1-methyl-4-aryl-1,2,3,6-tetrahydropyridines. 136 75

Previous studies from this laboratory demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent neurotoxicity to dopaminergic neurons in mice produced by systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, Turski et al. [Nature 349, 414-418 (1991)] reported that extended treatment of rats with NMDA receptor antagonists (six injections at 4-h intervals) did prevent the loss of nigral dopaminergic neurons resulting from an intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of MPTP. The present studies examined if a similar extended treatment with MK-801 would protect mice from the neurotoxicity of systemically administered MPTP. Six intraperitoneal injections of MK-801 given at 4-h intervals did not protect mice against the MPTP-induced neostriatal dopamine loss measured 1 week after treatment. In other experiments, designed to replicate and expand on the results of Turski et al. (1991), the extended treatment of rats with MK-801 did not prevent MPP(+)-induced cell loss in the infused substantia nigra pars compacta or the dopamine depletion in the ipsilateral neostriatum at 7-11 days after MPP+ infusion. These results do not support the hypothesis that NMDA receptors are involved with MPTP/MPP(+)-induced neurodegeneration.
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PMID:MK-801 fails to protect against the dopaminergic neuropathology produced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice or intranigral 1-methyl-4-phenylpyridinium in rats. 156 Feb 47

The conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to its toxic 1-methyl-4-phenylpyridinium (MPP+) metabolite catalyzed by monoamine oxidase (MAO) type B is likely to occur within glial cells in the central nervous system. In this study, primary cultures of mouse astrocytes were used to assess the biochemical and toxic consequences of exposure to MPTP. MPTP caused a concentration-dependent loss of cell viability. This effect was probably due to the intracellular generation of MPP+, because cytotoxicity was prevented by preincubation of astrocytes in the presence of MAO inhibitors. After addition of 250 microM MPTP, loss of cell viability was preceded by an increased rate of glucose utilization and lactate accumulation, and by depletion of ATP. The ratio between the rates of lactate production (0.37 mM/hr) and glucose consumption (0.2 mM/hr) was 1.85, indicating that most of the glucose present in the medium was stoichiometrically converted to lactate via glycolysis. A remarkable correlation was found between ATP depletion and cytotoxicity caused by MPTP, and, when astrocytes were incubated in glucose-free medium, both ATP depletion and loss of viability occurred more rapidly. Finally, even after exposure for several days, astrocyte death could be prevented by washing MPTP from the incubation medium, suggesting that MPP(+)-induced mitochondrial damage may be reversible. We conclude that prolonged exposure of astrocytes to MPTP may result in loss of viability via the MAO-dependent generation of MPP+ and the ability of this toxic metabolite to impair mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes. 156 Mar 84

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

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

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its oxidized metabolite, and two recently synthesized 2'-alkyl derivatives of MPTP (methyl and ethyl), found to be more toxic in vivo in mice, have been compared in two neuroblastoma hybrid cell lines (NCB-20 and 140-3) that express the B form of monoamine oxidase (MAO), as tissue culture models for the mode of action of MPTP in the central nervous system. Unlike previously reported studies with cultured cells of neuronal origin expressing only MAO A, both of these cell lines were sensitive to MPTP. Consistent with the in vivo findings, the 2'-alkyl derivatives were much more toxic than MPTP and comparable to the oxidized metabolite MPP+ in their effects on cell survival and morphology. The cells could be protected against the reduced toxins, but not MPP+, by either the MAO A selective inhibitor, clorgyline or the MAO B selective inhibitor, deprenyl. The effectiveness of the MAO inhibitors in blocking the action of the reduced toxins was consistent with their ability to inhibit MAO activity in the cell cultures, but did not reflect MAO-substrate specificity of the toxins. Inhibitors of serotonin and dopamine uptake, which have been found to protect against MPTP toxicity in vivo, were generally ineffective in the cell cultures, with the exception of a marginal increase in survival of MPP(+)-treated 140-3 cells in the presence of the serotonin uptake inhibitor fluoxetine. These findings are discussed in relation to proposed in vivo mechanisms of MPTP cytotoxicity.
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PMID:Toxicity of MPTP and structural analogs in clonal cell lines of neuronal origin expressing B type monoamine oxidase activity. 177 93

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, it has been postulated that (a) MPTP-like toxin(s) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) may induce Parkinson's disease. As the neuronal degeneration in MPTP-induced parkinsonism is thought to be caused by the inhibition of the mitochondrial respiration by 1-methyl-4-phenylpyridinium ion (MPP+), we studied the effects of TIQ-like alkaloids including dopamine-derived ones on the mitochondrial respiration using mouse brains. TIQ, tetrahydropapaveroline (THP), and tetrahydropapaverine (THPV) produced significant inhibition of the state 3 and 4 respiration and respiratory control ratio supported by glutamate + malate, the activity of Complex I and the ATP synthesis. Among those compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were quite similar to that of MPP+. Our results support the hypothesis that (a) MPTP- or MPP(+)-like substance(s) may be responsible for the nigral degeneration in Parkinson's disease.
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PMID:Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain. 197 53

The relationships between mitochondrial transmembrane potential, ATP concentration, and cytotoxicity were evaluated after exposure of isolated rat hepatocytes to different mitochondrial poisons. Both the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its fully oxidized metabolite, the 1-methyl-4-phenylpyridinium (MPP+) ion, caused a concentration- and time-dependent depolarization of mitochondrial membranes which followed ATP depletion and preceded cytotoxicity. The effect of MPTP, but not that of MPP+, was prevented by deprenyl, an inhibitor of MPTP conversion to MPP+ via monoamine oxidase type B. Addition of fructose to the hepatocyte incubations treated with either MPTP or MPP+ counteracted the loss of mitochondrial transmembrane potential. Fructose was also effective in protecting against the mitochondrial membrane depolarization as well as ATP depletion and cytotoxicity induced by antimycin. A, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, and valinomycin. Data confirm the key role played by MPP(+)-induced mitochondrial damage in MPTP toxicity and indicate that (i) ATP produced via the glycolytic pathway can be utilized by hepatocytes to maintain mitochondrial electrochemical gradient, and (ii) a loss of mitochondrial membrane potential may occur only when supplies of ATP are depleted.
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PMID:Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes. 212 6

This is a review of reserpine, haloperidol, and various phenothiazines that produce parkinsonism and other movement disorders. The by-products of illicit meperidine synthesis, MPTP and its more sinister companion, MPP, are also discussed. Movement disorders, transient or fixed, frank parkinsonism and/or dyskinesia, due to a variety of other medications and toxic agents are included. These are methanol, lithium, methyldopa, antimetabolites, antidepressants, sympathomimetic anorexiants, some types of antihistamines, and various combinations of agricultural chemicals.
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PMID:Drug-induced parkinsonism and other movement disorders. 219 87

In a previous study conducted over six months, we demonstrated that 1-methyl-4-phenylpyridinium ion (MPP+) the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, chronically infused (10 micrograms/24 h for seven days) into one median forebrain bundle of the rat can cause long-lasting damage to the nigrostriatal dopamine system. The present study was carried out in animals 18-19 months after MPP+ infusion to determine firstly, if the lesion was indeed permanent and secondly, if embryonic nigral dopamine suspension grafts implanted into the dopamine-denervated neostriatum can reverse the neurochemical and behavioural deficits induced by MPP+. All the animals within the MPP(+)-lesioned group showed robust contralateral and ipsilateral turning in response to apomorphine (0.05 mg/kg) and methamphetamine (2.5 mg/kg), respectively, at each time point of testing. In the grafted animals there was a progressive significant reduction in the number of rotations in response to both apomorphine and methamphetamine over the three-month test period. Autoradiographic analysis of [125I]sulpiride binding to striatal sections showed a 27% increase in dopamine D2 receptor density in the ipsilateral striatum of MPP(+)-lesioned animals. This increase in D2 receptor density was completely abolished by the dopamine grafts so that the D2 receptor density in the grafted striatum was similar to the contralateral striatum of MPP(+)-lesioned animals. This increase in D2 receptor density was completely abolished by the dopamine grafts so that the D2 receptor density in the grafted striatum was similar to the contralateral striatum of the grafted animals or the ipsilateral striatum of control non-lesioned animals. In all the animals of the lesioned and grafted groups there was a complete loss of dopamine neurons in the ipsilateral substantia nigra as demonstrated by tyrosine hydroxylase-immunohistochemistry and in-situ hybridization histochemistry. In all the animals that received nigral dopamine grafts, numerous cells were localized within the grafts which contained tyrosine hydroxylase immunoreactivity and tyrosine hydroxylase mRNA. Moreover, immunohistochemical staining showed a dense network of tyrosine hydroxylase-positive fibres within the grafted striatum. The results of the present study are important in two respects. Firstly, they demonstrate that MPP+ infusions into the rat nigrostriatal dopamine pathway can produce a permanent degeneration of nigral dopamine neurons. Thus, in animals assessed 18-19 months after the initial MPP(+)-lesion there was no significant behavioural or neurochemical compensation with time. Secondly, the results clearly show that embryonic nigral dopamine grafts implanted into the dopamine-denervated striatum can reverse the behavioural and neurochemical deficits induced by MPP+.
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PMID:Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway--III. Reversal by embryonic nigral dopamine grafts. 224 21


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