Abstract

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 (ΔΨm), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP⁺ (5 μM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their ΔΨm. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP⁺ to dopaminergic neurons, depolarized ΔΨm 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 ΔΨm 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.