Interactions of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidases
TLDR
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates.Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates. The nigrostriatal toxicity is not due to MPTP itself but to one or more oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or 'suicide' process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme.read more
Citations
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Mitochondria in the aetiology and pathogenesis of Parkinson's disease.
TL;DR: Insights into the aetiology and pathogenesis of PD provide hope that drugs or cocktails of drugs that might successfully intervene in the pathogenesis and slow the progression of the disease can be derived from the study of the converging rather than diverging pathways to cell dysfunction and death.
Journal ArticleDOI
Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds
Keith F. Tipton,Thomas P. Singer +1 more
TL;DR: The present account will concentrate on more recent discoveries concerning the mechanism by which MPTP exerts its selective neurotoxic effects and the unresolved problems that remain.
Journal ArticleDOI
MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease
TL;DR: This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP and the relevance of the MPTP model to idiopathic Parkinson's disease is discussed.
Journal ArticleDOI
Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
TL;DR: Rapid progress in clarifying the individual steps leading to the neuropathological symptoms has been remarkable and a plausible mechanistic picture has emerged so that the time seems right to review current knowledge of the individual biochemical events involved in the expression of the selective neurotoxicity of MPTP.
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Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey.
TL;DR: This study demonstrates that in the rhesus monkey MPTP mimicked, in addition to the profound striatal dopamine loss, some of the extrastriatal dopamine, noradrenaline and serotonin changes often seen in the brain of patients with idiopathic Parkinson's disease.
References
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Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis
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A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
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Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity.
TL;DR: Blockage of dopamine uptake by mazindol prevents MPTP-induced damage to nigrostriatal dopamine neurons, indicating that MPP+ concentration into dopamine neurons explains their selective destruction by MPTP.
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Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.
TL;DR: The neurotoxic chemical MPTP is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min, and the major metabolite has been identified as the 1-methyl-4- phenylpyridinium species.