Biochemical Events in the Development of Parkinsonism Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (original) (raw)
1987, Journal of Neurochemistry
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The paper reviews the biochemical mechanisms leading to the neurotoxicity associated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP), a compound linked to the development of parkinsonism. It discusses the bioactivation of MPTP through the activities of monoamine oxidase (MAO) enzymes, specifically emphasizing the role of MAO B in converting MPTP to its toxic derivatives, which contribute to neuronal damage. The findings suggest that understanding these biochemical events could offer insights into the pathogenesis of idiopathic Parkinson's disease and inform potential therapeutic approaches.
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Neuroscience Letters, 1986
tetrahydropyridine-l-methyl-4-phenylpyridinium-dopaminemonoamine oxidase B-human brain-(-)-deprenyl-rat-mouse A new in vitro radiometric method has been developed for the direct assay of the oxidation of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to its main neurotoxic metabolite l-methyl-4-phenylpyridinium. This assay has been used to show that the rate of oxidation of MPTP parallels that of phenylethylamine in a range of human and rodent tissues, providing strong evidence that this reaction is predominantly catalysed by monoamine oxidase B (MAO-B). In human brain the reaction was inhibited by selective doses of the MAO-B inhibitor (-)-deprenyl. When dopamine was added to the incubation mixture. products of MPTP oxidation appeared to form a complex with it.
In vitro oxidation of MPTP by primate neural tissue: A potential model of MPTP neurotoxicity
Neurochemistry International, 1985
The compound 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome in humans and primates. We have previously found that metabolism of MPTP to a quaternary species is necessary for the expression of its neurotoxic effects. We now report that the metabolism of MPTP occurs in primate brain tissue in vitro, and present a model of MPTP neurotoxicity which incorporates our findings to date. Since the toxicity of MPTP is metabolism dependent, we propose that the in vitro metabolism of MPTP by brain tissue should provide a useful model for studying selected aspects of MPTP neurotoxicity.
Mechanism of the neurotoxicity of MPTP
FEBS Letters, 1990
This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.
Mechanism of the neurotoxicity of MPTP: An update
Febs Letters, 1990
This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.
Toxicology, 1988
It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.
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