Inhibition of 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells by sulfonylurea glibenclamide.
The present study investigates the effect of sulfonylurea glibenclamide on the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+) in differentiated PC12 cells in relation to changes in the mitochondrial membrane permeability. Glibenclamide and tolbutamide reduced the MPP+-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 5-10 microM. Despite the toxic effect at 20 microM, sulfonylureas showed an inhibitory effect. N-Acetylcysteine, superoxide dismutase, catalase, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and Mn(III) tetrakis(4-benzoic acid)porphyrin chloride inhibited the cytotoxicity of MPP+. Glibenclamide attenuated the nuclear damage, changes in the mitochondrial membrane permeability, caspase-3 activation and formation of reactive oxygen species due to MPP+ in PC12 cells. The results show that glibenclamide may reduce the MPP+-induced viability loss in PC12 cells by suppressing the changes in the mitochondrial membrane permeability, leading to the release of cytochrome c and subsequent activation of caspase-3, which are associated with the increased reactive oxygen species formation and depletion of GSH.
Lee
Chung Soo
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
Kim
Yun Jeong
YJ
Ko
Hyun Hee
HH
Han
Eun Sook
ES
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010539:Permeability / Q000187:drug effects; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014044:Tolbutamide / Q000494:pharmacology
D001565:Benzoates; D007093:Imidazoles; D011166:Porphyrins; D017382:Reactive Oxygen Species; C480958:tetrakis(4-benzoic acid)porphyrin; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D045304:Cytochromes c; D014044:Tolbutamide; D002374:Catalase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium; D005905:Glyburide; D000111:Acetylcysteine