[The bases of MPTP neurotoxicity]

Self-administration of MPTP to man results in the appearance of a parkinsonian syndrome closely related, if not identical, to idiopathic Parkinsonism. The effects of MPTP administration to different animal species are presented and differences of MPTP toxicity with strain and age are underlined. MPTP interacts with the A and B forms of MAO. It is a substrate and also an inhibitor of both forms of MAO, its main inhibitory effect resulting, however, in an irreversible inhibition of MAO-B. Evidence that the neurotoxic effect of MPTP can be prevented by a pretreatment with MAO inhibitors of the B type is presented. Differences in the metabolic pathway of MPTP, at the periphery and centrally, are presented and the relationship between MPTP metabolism and neurotoxic effect in different species is highlighted. Prevention or potentiation of MPTP-induced neurotoxicity by various agents are also reported. Neurotoxicity of MPTP has been attributed to the formation of MPP+ by MAO-B, for the first step at least. Various hypotheses proposed to explain MPP+-induced neurotoxic effects are presented and discussed, the inhibition of mitochondrial respiration being that whose experimental basis appears to be the most relevant. By comparison with the effects produced by chemically-related analogues, the establishment of a relationship between some molecular characteristics of MPTP and its neurotoxic activity is proposed. Finally, the possible role of other endogenous or exogenous agents in the appearance of various neurologic syndromes is also discussed.