Neuroprotective effects of the antifungal drug clotrimazole

Pretreatment with 10 muM of the antifungal drug clotrimazole potently reduced the death of cultured rat cerebellar granule cells induced by oxygen/glucose deprivation, and the excitotoxic effect of glutamate on cultured hippocampal neurons and cerebellar granule cells. In patch-clamped hippocampal pyramidal neurons, 10-50 muM clotrimazole caused a decrease in the amplitude of N-methyl-D-aspartate (NMDA) receptor-mediated currents. Glutamate induced intracellular Ca2+ overload, as measured by Fluo-3 confocal fluorescence imaging, while clotrimazole reduced Ca2+ overload and promoted the recovery of intracellular calcium homeostasis after glutamate treatment Using tetra-methylrhodamine ethyl ester fluorescence as a marker of mitochondrial membrane potential we found that clotrimazole prevented the glutamate-induced loss of mitochondrial membrane potential. Our data provide evidence that the protective effect of clotrimazole against oxygen/glucose deprivation and excitotoxicity is due to the ability of this drug to partially block NMDA receptor-gated channel, thus causing both reduced calcium overload and lower probability of the mitochondrial potential collapse. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.