Prostaglandin analogue misoprostol attenuates neurotoxin 1-methyl-4-phenylpyridinium-induced mitochondrial damage and cell death in differentiated PC12 cells.
Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The present study assessed the preventive effect of a prostaglandin E(1) analogue misoprostol against the toxicity of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) with respect to the mitochondria-mediated cell death process and oxidative stress. MPP(+) induced the nuclear damage, the changes in the mitochondrial membrane permeability, the formation of reactive oxygen species and the depletion of GSH, which leads to cell death in differentiated PC12 cells. Misoprostol prevented the toxic effect of MPP(+). Treatment with misoprostol significantly attenuated the MPP(+)-induced mitochondrial membrane permeability change that leads to the increase in pro-apoptotic Bax and Cytochrome c levels, and subsequent caspase-3 activation. The protective effect of misoprostol may be supported by the inhibitory effect of prostaglandin E(1) on the MPP(+) toxicity. Misoprostol significantly attenuated another parkinsonian neurotoxin rotenone-induced cell death. The results show that misoprostol may prevent the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to the Cytochrome c release and caspase-3 activation. The preventive effect seems to be ascribed to the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.
Choi
Eun Joo
EJ
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
Han
Jeong Ho
JH
Lee
Chung Soo
CS
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000527:Alprostadil / Q000031:analogs & derivatives*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity; D016595:Misoprostol / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D016166:Free Radical Scavengers; D006540:Herbicides; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D016595:Misoprostol; D000527:Alprostadil; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium