MPTP-induced Parkinsonism in Human and Non-human Primates--clinical and Experimental Aspects

In this review, we describe the discovery of a new neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP, which appears to be highly selective for the substantia nigra of human and non-human primates. This compound appears to produce a "pure" parkinsonian state more consistently than most, if not all previously described neurotoxins. Identification of its unique properties has already led to the development of an animal model for Parkinson's disease in the monkey. In this paper we review the history of the compound, and describe its clinical effects in man and monkeys. Experiments are reviewed which suggest that the "4-5" double bond in the nitrogen-containing ring is key for this compound to exert its toxic effects, probably serving as a starting point for oxidation of MPTP to its quaternary amine, 1-methyl-4-phenylpyridinium ion (MPP+). MPTP appears to be rapidly converted to the latter compound in all tissues studied to date, including brain. We believe that this newly recognized nigrotoxin holds promise as a tool for the study of Parkinson's disease and the nigrostriatal dopaminergic system of the brain.