title: Econazole attenuates cytotoxicity of 1-methyl-4-phenylpyridinium by suppressing mitochondrial membrane permeability transition.
abstract: Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The effect of econazole against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells was assessed in relation to the mitochondrial membrane permeability changes. Treatment of PC12 cells with MPP(+) resulted in the 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 (ROS) and depletion of GSH. Econazole (0.25-2.5 microM) inhibited the cytotoxicity of MPP(+) or rotenone. The addition of econazole (0.5 microM) significantly attenuated the MPP(+)-induced mitochondrial damage, elevation of intracellular Ca(2+) level and cell death. However, because of the cytotoxicity, econazole at 5 microM did not attenuate the toxicity of MPP(+). The results show that econazole at the low concentrations may reduce the MPP(+)-induced viability loss in PC12 cells by suppressing the mitochondrial permeability transition, leading to activation of caspase-3 and the elevation of intracellular Ca(2+) levels, which are associated with the increased formation of ROS and 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: Soo Bin
authors.initials: SB
authors.lastname: Yim
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Song
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Han
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004464:Econazole / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D006540:Herbicides / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects*; D016716:PC12 Cells / Q000648:ultrastructure; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D006540:Herbicides; D017382:Reactive Oxygen Species; D004464:Econazole; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium