PT  - JOURNAL ARTICLE
AU  - Ken Nakamura
AU  - Vytautas P. Bindokas
AU  - Jeremy D. Marks
AU  - David A. Wright
AU  - David M. Frim
AU  - Richard J. Miller
AU  - Un Jung Kang
TI  - The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited
AID  - 10.1124/mol.58.2.271
DP  - 2000 Aug 01
TA  - Molecular Pharmacology
PG  - 271--278
VI  - 58
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/58/2/271.short
4100  - http://molpharm.aspetjournals.org/content/58/2/271.full
SO  - Mol Pharmacol2000 Aug 01; 58
AB  - 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.