Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors.
The cause of dopaminergic neurodegeneration in Parkinson's disease remains unclear, but may involve both oxidative stress and mitochondrial complex I inhibition. We have demonstrated that complex I inhibitors, including rotenone, MPP+, isoquinoline and tetrahydroisoquinoline, induce apoptosis in PC12 and SK-N-MC dopaminergic cell lines which was decreased by pretreatment with N-acetylcysteine, TEMPO, dihydrolipoic acid or pyrrolidine dithiocarbamate. These results indicate that the pathway leading to apoptosis following complex I inhibition involves free radical generation. The free radical generation may result directly from inhibition of the mitochondrial respiratory chain or indirectly during the apoptotic process itself. This has important implications for our understanding of the relationship between complex I deficiency and oxidative stress and neurodegeneration in Parkinson's disease.
Seaton
T A
TA
University Department of Clinical Neuroscience, Royal Free Hospital School of Medicine, London, UK.
Cooper
J M
JM
Schapira
A H
AH
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000975:Antioxidants; D015259:Dopamine Agents; D016166:Free Radical Scavengers; D007546:Isoquinolines; D014475:Uncoupling Agents; D012402:Rotenone; D000255:Adenosine Triphosphate; D007655:Ketoglutarate Dehydrogenase Complex; D016660:NAD(P)H Dehydrogenase (Quinone); C039109:isoquinoline; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine