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.
Footnotes
- Received September 21, 1999.
- Accepted May 4, 2000.
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Send reprint requests to: Un Jung Kang, M.D., MC 2030, S225B, Department of Neurology, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637. E-mail:u-kang{at}uchicago.edu
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This research was supported by the Brain Research Foundation, Louis R. Block Fund, National Parkinson Foundation, Parkinson Disease Foundation, United Parkinson Foundation, and U.S. Public Health Service Grant NS07113.
- The American Society for Pharmacology and Experimental Therapeutics
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