Summary Several biochemical abnormalities have been described in the brains of patients with Parkinson's disease (PD), including oxidative stress and mitochondrial dysfunction. The identification of specific gene mutations that cause PD has reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and the sporadic forms of the disease. The proteins that are associated with familial PD—PTEN-induced putative kinase 1 (PINK1), DJ-1, α-synuclein, leucine-rich repeat kinase 2, and, possibly, parkin—are either mitochondrial proteins or are associated with mitochondria, and all interface with the pathways of oxidative stress and free radical damage. 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.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(07)70327-7.pdf

Mitochondria in the aetiology and pathogenesis of Parkinson's disease.

The discovery that 1 -methyl4-phenyl1,2,3,6-tetrahydropyndine (MPTP), a contaminant of a synthetic pethidine analogue sold as a street drug, produced a condition resembling Parkinson’s disease has been described in detail (for reviews, see Langston, 1985; Snyder and DAmato, 1986). MPTP was shown to cause a selective destruction of nigrostriatal dopaminergic neurons in primates and some other animal species, and this stimulated a great deal ofwork on the mechanisms involved in its neurotoxic effects and their possible relationship to idiopathic Parkinson’s disease. Earlier work on the mechanism by which MPTP exerts its selective neurotoxic effects has been reviewed before, and the present account will concentrate on more recent discoveries concerning its biochemical actions and the unresolved problems that remain.

Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds

MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease

Although only 3 years have passed since the appearance of the first report linking the presence of 1 -methyl-4-phenyl1,2,3,6-tetrahydropyriidine (MPTP) in preparations of an illicitly synthesized meperidine analog to the appearance of parkinsonian symptoms (Langston et al., 1983), progress in clarifying the individual steps leading to the neuropathological symptoms has been remarkable. Although some interesting questions still remain, 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. One reason for the rapid progress has been the worldwide interest generated by the availability of the first animal model for parkinsonism and the hope that elucidation of the mechanism of the neurotoxicity of MPTP may yield clues to some of the causes of idiopathic Parkinson’s disease. To the extent that this has been achieved, the accidental presence of this potent neurotoxin in some batches of “new heroin” may benefit mankind, despite the tragic consequences to the individuals exposed to it and the alarming social and medical problems of “designer drugs” that it has brought into sharp focus.

Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey.

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.

/pdf/interactions-of-the-neurotoxic-amine-1-methyl-4-phenyl-1-2-3-iivf1olvw0.pdf

N Castagnoli

Papers

Interactions of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidases