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 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.
Nakamura
K
K
Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Bindokas
V P
VP
Marks
J D
JD
Wright
D A
DA
Frim
D M
DM
Miller
R J
RJ
Kang
U J
UJ
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D007150:Immunohistochemistry; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D006540:Herbicides; D017382:Reactive Oxygen Species; D011954:Receptors, Dopamine; D012402:Rotenone; D013481:Superoxides; D009245:NADH Dehydrogenase; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium