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.