Cyclosporin inhibition of apoptosis induced by mitochondrial complex I toxins.
The cause of dopaminergic cell death in Parkinson's disease (PD) remains unknown, but may involve oxidative stress and mitochondrial complex I deficiency. Opening of the permeability transition pore and disruption of the mitochondrial transmembrane potential are known to be common events in the apoptotic pathway. Cyclosporin A and its non-immunosuppressant analogue, N-methyl-4-valine cyclosporin inhibit the opening of the mitochondrial megachannel. Complex I inhibitors, including MPP+, are known to induce both apoptosis in cell culture and parkinsonism in man and other primates. The present study using propidium iodide and FITC-TUNEL staining to identify apoptotic cells, demonstrates that rotenone, MPP+ and tetrahydroisoquinoline induce apoptosis in PC12 cells. Apoptosis induced by these agents was decreased by cyclosporin A and N-methyl-4-valine cyclosporin. Thus, apoptosis induced by inhibitors of mitochondrial complex I is probably mediated by permeability pore opening and collapse of the mitochondrial membrane potential. This observation may allow the development of novel neuroprotective strategies in disorders that may involve mitochondrial dysfunction and apoptotic cell death.
Seaton
T A
TA
University Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, London, NW3 2PF, UK.
Cooper
J M
JM
Schapira
A H
AH
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004396:Coloring Agents; D016572:Cyclosporine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D020287:In Situ Nick-End Labeling; D007425:Intracellular Membranes / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism; D011419:Propidium; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D004396:Coloring Agents; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D014475:Uncoupling Agents; D012402:Rotenone; D011419:Propidium; D016572:Cyclosporine; D016660:NAD(P)H Dehydrogenase (Quinone); C050025:cyclosporin H; D016650:Fluorescein-5-isothiocyanate; D015655:1-Methyl-4-phenylpyridinium