Neuroprotective effects of the antifungal drug clotrimazole

• Published in: Neuroscience 2002-01, Vol.113 (1), p.47-53
• Main Authors: Isaev, N.K, Stelmashook, E.V, Dirnagl, U, Andreeva, N.A, Manuhova, L, Vorobjev, V.S, Sharonova, I.N, Skrebitsky, V.G, Victorov, I.V, Katchanov, J, Weih, M, Zorov, D.B
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - pharmacology; Calcium - metabolism; Cell Culture Techniques; Cell Hypoxia - drug effects; Cerebellum - cytology; Cerebellum - drug effects; cerebral ischemia; Clotrimazole - pharmacology; cultured neurons; Glucose - deficiency; glutamate; Glutamic Acid - toxicity; Hippocampus - cytology; Hippocampus - drug effects; Membrane Potentials - drug effects; Microscopy, Confocal; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neuroprotective Agents - pharmacology; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(02)00164-1

Pretreatment with 10 μM 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 μM clotrimazole caused a decrease in the amplitude of N-methyl- D-aspartate (NMDA) receptor-mediated currents. Glutamate induced intracellular Ca 2+ overload, as measured by Fluo-3 confocal fluorescence imaging, while clotrimazole reduced Ca 2+ overload and promoted the recovery of intracellular calcium homeostasis after glutamate treatment. Using tetramethylrhodamine 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.