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

1-Methyl-4-phenylpyridinium (MPP+) is selectively toxic to dopaminergic neu rons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP+ t oxicity and the pathogenesis of PD. MPP+ can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochon drial depolarization and generation of reactive oxygen species. However, MP P+ toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, w e examined the effects of MPP+ on survival, mitochondrial membrane potentia l (Delta Psi m), and superoxide and reduced glutathione levels in individua l dopaminergic and nondopaminergic mesencephalic neurons. MPP+ (5 mu M) sel ectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their Delta Psi m. In contrast, the specific complex I inhibit or rotenone, at a dose (20 nM) that was less toxic than MPP+ to dopaminergi c neurons, depolarized Delta Psi m to a greater extent than MPP+. In additi on, neither rotenone nor MPP+ increased superoxide in dopaminergic neurons, and MPP+ failed to alter levels of reduced glutathione. Therefore, we conc lude that increased superoxide and loss of Delta Psi m may not represent pr imary events in MPP+ toxicity, and complex I inhibition alone is not suffic ient to explain the selective toxicity of MPP+ to dopaminergic neurons. Cla rifying the effects of MPP+ on energy metabolism may provide insight into t he mechanism of dopaminergic neuronal degeneration in PD.