Protective effect of melatonin on rotenone plus Ca2+-induced mitochondrial oxidative stress and PC12 cell death.
Chronic systemic inhibition of mitochondrial respiratory chain complex I by rotenone causes nigrostriatal dopaminergic degeneration in rats, producing an in vivo experimental model of Parkinson's disease. We recently showed that micromolar Ca2+ concentrations strongly stimulate the release of reactive oxygen species in rotenone-treated isolated rat brain mitochondria. In the present work, we show that the natural antioxidant melatonin inhibits Ca2+ plus rotenone-induced oxidative stress in isolated rat brain mitochondria. In addition, the Ca2+ ionophore A23187 strongly potentiates rotenone-induced death of intact cultured pheochromocytoma (PC12) cells, in a mechanism sensitive to melatonin. Moreover, melatonin inhibits the detection of reactive oxygen species release in PC12 cells treated with rotenone plus A23187. Melatonin does not alter free Ca2+ concentrations or the inhibitory effect of rotenone on mitochondrial complex I. We conclude that micromolar Ca2+ concentrations stimulate neuronal cell death induced by mitochondrial complex I inhibition in a mechanism involving oxidative stress, preventable by the antioxidant melatonin.
Sousa
Solange C
SC
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.
Castilho
Roger F
RF
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism / Q000493:pharmacokinetics; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology*; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
D000975:Antioxidants; D007476:Ionophores; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D000001:Calcimycin; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D008550:Melatonin; D010100:Oxygen; D002118:Calcium