The parkinsonian toxin MPTP: Action and mechanism

MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's disease (PD). After systemic administration of MPTP, its active metabolite, MPP⁺, accumulates within SNpc DA neurons, where it inhibits ATP production and stimulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these, is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis. The process of nitration inactivates TH and, consequently dopamine production. Peroxynitrite also nicks DNA, which, in tum, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes cell energy stores. This latter event aggravates the preexisting energy failure due to MPP⁺-induced mitochondrial respiration blockade and precipitates cell death. Altogether, these findings support the view that MPTP's deleterious cascade of events include mitochondrial respiration deficit, oxidative stress, and energy failure. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD.