Differential involvement of mitochondrial permeability transition in cytotoxicity of 1-methyl-4-phenylpyridinium and 6-hydroxydopamine.
Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The aim of the present study was to assess the influence of the mitochondrial membrane permeability transition inhibition against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) and 6-hydroxydopamine (6-OHDA) in relation to the mitochondria-mediated cell death process and role of oxidative stress. Both MPP(+) and 6-OHDA induced the nuclear damage, the changes in the mitochondrial membrane permeability, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in differentiated PC12 cells. Cyclosporin A (CsA), trifluoperazine and aristolochic acid, inhibitors of mitochondrial permeability transition, significantly attenuated the MPP(+)-induced mitochondrial damage leading to caspase-3 activation, increased oxidative stress and cell death. In contrast to MPP(+), the cytotoxicity of 6-OHDA was not reduced by the addition of the mitochondrial permeability transition inhibitors. The results show that the cytotoxicity of MPP(+) may be mediated by the mitochondrial permeability transition formation, which is associated with formation of reactive oxygen species and the depletion of GSH. In contrast, the 6-OHDA-induced cell injury appears to be mediated by increased oxidative stress without intervention of the mitochondrial membrane permeability transition.
Lee
Chung Soo
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
Park
Woo Jae
WJ
Ko
Hyun Hee
HH
Han
Eun Sook
ES
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006892:Hydroxydopamines / Q000633:toxicity*; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
D003574:Cytochrome c Group; D006892:Hydroxydopamines; D017382:Reactive Oxygen Species; C076615:cytochrome c''; D014268:Trifluoperazine; D016572:Cyclosporine; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium