Metabolic activation and mechanisms of MPTP toxicity

Abstract

In 1982 the abrupt onset of a severe Parkinsonian syndrome in young drug addicts led to the discovery of the neurotoxicant l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) (Langston et al., 1983). The great interest prompted by this discovery within the scientific community as well as the general public is quite justified if the following two considerations are made. First, MPTP-induced Parkinsonism in humans is virtually indistinguishable from the idiopathic disease. Patients who injected themselves with a ‘synthetic heroin’ contaminated by MPTP exhibited all of the motor features of Parkinsons disease (PD), including the classic triad of tremor, bradykinesia and rigidity (Langston et al., 1983). Secondly, administration of MPTP to primates has provided us with the closest animal model for PD. For example, exposure of monkeys to this compound causes a severe degeneration of dopaminergic neurones in the zona compacta of the substantia nigra (Burns et al., 1983; Langston et al., 1984a); this, of course, represents the major pathological feature of PD as well.