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 mu M) inhibited the cytotoxicity of MPP+ or rotenone. The addition of econazole (0.5 mu M) significantly attenuated the MPP+-induced mitochondrial damage, elevation of intracellular Ca2+ level and cell death. However, because of the cytotoxicity, econazole at 5 mu M 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 Ca2+ levels, which are associated with the increased formation of ROS and depletion of GSH. (c) 2006 Elsevier Inc. All rights reserved.