title: Inhibition of MPP+-induced mitochondrial damage and cell death by trifluoperazine and W-7 in PC12 cells.
abstract: Opening of the mitochondrial permeability transition pore has been recognized to be involved in cell death. The present study investigated the effect of trifluoperazine and W-7 on the MPP+-induced mitochondrial damage and cell death in undifferentiated PC12 cells. Calmodulin antagonists (trifluoperazine, W-7 and calmidazolium) at 0.5-1 microM significantly reduced the loss of cell viability in PC12 cells treated with 500 microM MPP+. Trifluoperazine and W-7 (0.5-1 microM) inhibited the nuclear damage, the loss of the mitochondrial transmembrane potential followed by cytochrome c release, and the elevation of intracellular Ca2+ levels due to MPP+ in PC12 cells and attenuated the formation of reactive oxygen species and the depletion of GSH. Calmodulin antagonists at 5-10 microM exhibited a cytotoxic effect on PC12 cells, and compounds at 10 microM did not attenuate cytotoxicity of MPP+. Calmodulin antagonists (0.5-1 microM) significantly reduced rotenone-induced mitochondrial damage and cell death, whereas they did not attenuate cell death and elevation of intracellular Ca2+ levels due to H2O2 or ionomycin. The results show that trifluoperazine and W-7 exhibit a differential inhibitory effect against cytotoxicity of MPP+ depending on concentration. Both compounds at the concentrations less than 5 microM may attenuate the MPP+-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability and by lowering the intracellular Ca2+ levels.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.uk
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
authors.forename: Se Young
authors.initials: SY
authors.lastname: Park
authors.forename: Hyun Hee
authors.initials: HH
authors.lastname: Ko
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Song
authors.forename: Yong Kyoo
authors.initials: YK
authors.lastname: Shin
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Han
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D007202:Indicators and Reagents; D008928:Mitochondria / Q000187:drug effects*; D016716:PC12 Cells; D010539:Permeability; D011726:Pyridinium Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D002147:Calmodulin; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011726:Pyridinium Compounds; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D012402:Rotenone; D014268:Trifluoperazine; C026560:1-(4-methoxyphenyl)pyridinium; C017967:W 7; D045304:Cytochromes c; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D002118:Calcium