title: Differential modulation of 7-ketocholesterol toxicity against PC12 cells by calmodulin antagonists and Ca2+ channel blockers.
abstract: The present study assessed the influence of intracellular Ca2+ and calmodulin against the neurotoxicity of oxysterol 7-ketocholesterol in relation to the mitochondria-mediated cell death process and oxidative stress in PC12 cells. Calmodulin antagonists calmidazolium and W-7 prevented the 7-ketocholesterol-induced mitochondrial damage, leading to caspase-3 activation and cell death, whereas Ca2+ channel blocker nicardipine, mitochondrial Ca2+ uptake inhibitor ruthenium red, and cell permeable Ca2+ chelator BAPTA-AM did not reduce it. Exposure of PC12 cells to 7-ketocholesterol caused elevation of intracellular Ca2+ levels. Unlike cell injury, calmodulin antagonists, nicardipine, and BAPTA-AM prevented the 7-ketocholesterol-induced elevations of intracellular Ca2+ levels. The results show that the cytotoxicity of 7-ketocholesterol seems to be modulated by calmodulin rather than changes in intracellular Ca2+ levels. Calmodulin antagonists may prevent the cytotoxicity of 7-ketocholesterol by suppressing the mitochondrial permeability transition formation, which is associated with the increased formation of reactive oxygen species and the depletion of GSH.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
authors.forename: Woo Jae
authors.initials: WJ
authors.lastname: Park
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Han
authors.forename: Hyoweon
authors.initials: H
authors.lastname: Bang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007653:Ketocholesterols / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002147:Calmodulin; D007093:Imidazoles; D007653:Ketocholesterols; D013449:Sulfonamides; D012430:Ruthenium Red; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C031938:calmidazolium; D004533:Egtazic Acid; C017967:W 7; D014700:Verapamil; D009529:Nicardipine; C003001:7-ketocholesterol; D002118:Calcium