The parkinsonian toxin MPTP: action and mechanism

MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (D A) neurons as seen in Parkinson's disease (PD). After systemic administrati on of MPTP, its active metabolite, MPP+, accumulates within SNpc DA neurons , where it inhibits ATP production and stimulates superoxide radical format ion. The produced superoxide radicals react with nitric oxide (NO) to produ ce peroxynitrite, a highly reactive tissue-damaging species that damages pr oteins by oxidation and nitration. Only selected proteins appear nitrated, and among these, is found tyrosine hydroxylase (TH), the rate limiting enzy me in DA synthesis. The process of nitration inactivates TH and, consequent ly dopamine production. Peroxynitrite also nicks DNA, which, in turn, activ ates 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 bl ockade and precipitates cell death. Altogether, these findings support the view that MPTP's deleterious cascade of events include mitochondrial respir ation deficit. oxidative stress, and energy failure. Because of the similar ity between the MPTP mouse model and PD, it is tempting to propose that a s imilar scenario applies to the pathogenesis of PD.