7-Ketocholesterol enhances 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells.
The present study investigated the promoting effect of oxysterol 7-ketocholesterol against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells. 7-Ketocholesterol significantly enhanced the MPP(+)-induced nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species and depletion of GSH. N-Acetylcysteine, ascorbate, trolox, carboxy-PTIO and Mn-TBAP reduced the cytotoxic effect of MPP(+) in the presence of 7-ketocholesterol. The results indicate that 7-ketocholesterol shows a synergistic effect against the cytotoxic effect of MPP(+). 7-Ketocholesterol may enhance the MPP(+)-induced viability loss in PC12 cells by promoting the mitochondrial membrane permeability change, release of cytochrome c and subsequent activation of caspase-3, which is associated with the increased formation of reactive oxygen species and depletion of GSH. The findings suggest that 7-ketocholesterol as a promoting agent for the formation of mitochondrial permeability transition may enhance the toxic neuronal cell injury.
Kim
Y J
YJ
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea.
Han
J H
JH
Han
E S
ES
Lee
C S
CS
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D007653:Ketocholesterols / Q000633:toxicity*; D020267:MPTP Poisoning / Q000473:pathology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D016716:PC12 Cells; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D007653:Ketocholesterols; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D053148:Caspase 3; D005978:Glutathione; C003001:7-ketocholesterol