Neuroprotective Effect of KB-R7943 Against Glutamate Excitotoxicity is Related to Mild Mitochondrial Depolarization
KB-R7943, an inhibitor of a reversed Na+/Ca2+ exchanger, exhibits neuroprotection against glutamate excitotoxicity. Taking into consideration that prolonged exposure of neurons to glutamate induces delayed calcium deregulation (DCD) and irreversible decrease of mitochondrial membrane potential (Δψmit), we examined the effect of KB-R7943 on glutamate and kainate-induced [Ca2+]i and on Δψmit changes in rat cultured cerebellar granule neurons. 15 μmol/l KB-R7943 significantly delayed the onset of DCD in response to kainate but not in response to glutamate. In spite of [Ca2+]i overload, KB-R7943 considerably improved the [Ca2+]i recovery and restoration of Δψmit after glutamate and kainate washout and increased cell viability after glutamate exposure. In resting neurons, KB-R7943 induced a statistically significant decrease in Δψmit. KB-R7943 also depolarized isolated brain mitochondria and slightly inhibited mitochondrial Ca2+ uptake. These findings suggest that mild mitochondrial depolarization and diminution of Ca2+ accumulation in the organelles might contribute to neuroprotective effect of KB-R7943.
KeywordsNeuron Delayed calcium deregulation Na+/Ca2+ exchanger Mitochondria KB-R7943
We gratefully thank Prof. Boris Khodorov for helpful discussion of the experimental data. The study was supported by Russian Foundation of Basic Research, grants no. 08-04-01802a; 08-04-05072b to VGP and by NIH/NINDS R01 NS 050131 and a grant from Indiana Spinal Cord and Brain Injury Research Fund to NB.