KB-R7943, an inhibitor of a reversed Na(+)/Ca(2+) 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 (Deltapsi(mit)), we examined the effect of KB-R7943 on glutamate and kainate-induced [Ca(2+)](i) and on Deltapsi(mit) changes in rat cultured cerebellar granule neurons. 15 micromol/l KB-R7943 significantly delayed the onset of DCD in response to kainate but not in response to glutamate. In spite of [Ca(2+)](i) overload, KB-R7943 considerably improved the [Ca(2+)](i) recovery and restoration of Deltapsi(mit) after glutamate and kainate washout and increased cell viability after glutamate exposure. In resting neurons, KB-R7943 induced a statistically significant decrease in Deltapsi(mit). KB-R7943 also depolarized isolated brain mitochondria and slightly inhibited mitochondrial Ca(2+) uptake. These findings suggest that mild mitochondrial depolarization and diminution of Ca(2+) accumulation in the organelles might contribute to neuroprotective effect of KB-R7943.