CYCLOSPORINE-A DELAYS MITOCHONDRIAL DEPOLARIZATION-INDUCED BY N-METHYL-D-ASPAPARTE IN CORTICAL-NEURONS - EVIDENCE OF THE MITOCHONDRIAL PERMEABILITY TRANSITION

N-Methyl-D-aspartate causes a rapid increase in intracellular Ca2+ lea ding to collapse of the mitochondrial membrane potential and eventuall y cell death in cortical neurons. The aim of this study was to investi gate the mechanism responsible for mitochondrial depolarization using laser scanning confocal microscopy of single cultured rat cortical neu rons. To monitor mitochondrial membrane potential, neuronal mitochondr ia were labeled with tetramethylrhodamine methyl ester, a cationic flu orophore that accumulates in polarized mitochondria. In neurons cultur ed on poly-D-lysine-coated coverslips, N-methyl-D-aspartate caused mit ochondrial depolarization in 88% of cells in 30 min. Cyclosporin A, an inhibitor of the mitochondrial permeability transition, delayed depol arization in a dose-dependent manner (0.21 mu M). In neurons cultured on an astrocyte feeder layer, N-methyl-D-aspartate also caused mitocho ndrial depolarization. Cyclosporin A again delayed mitochondrial depol arization, although higher concentrations were needed. These data show for the first time that mitochondrial depolarization induced by N-met hyl-D-aspartate may be due to the induction of the mitochondrial perme ability transition. Copyright (C) 1996 IBRO. Published by Elsevier Sci ence Ltd.