The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited.

摘要

1-Methyl-4-phenylpyridinium (MPP(+)) is selectively toxic to dopaminergic neurons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP(+) toxicity and the pathogenesis of PD. MPP(+) can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochondrial depolarization and generation of reactive oxygen species. However, MPP(+) toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, we examined the effects of MPP(+) on survival, mitochondrial membrane potential (DeltaPsim), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP(+) (5 microM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their DeltaPsim. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP(+) to dopaminergic neurons, depolarized DeltaPsim to a greater extent than MPP(+). In addition, neither rotenone nor MPP(+) increased superoxide in dopaminergic neurons, and MPP(+) failed to alter levels of reduced glutathione. Therefore, we conclude that increased superoxide and loss of DeltaPsim may not represent primary events in MPP(+) toxicity, and complex I inhibition alone is not sufficient to explain the selective toxicity of MPP(+) to dopaminergic neurons. Clarifying the effects of MPP(+) on energy metabolism may provide insight into the mechanism of dopaminergic neuronal degeneration in PD.