Neuroprotective effects of the antifungal drug clotrimazole.
Pretreatment with 10 microM 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 microM 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.
Isaev
N K
NK
A.N. Belozersky Institute of Physico-Chemical Biology, Moscow Stat, Moscow, Russia.
Stelmashook
E V
EV
Dirnagl
U
U
Andreeva
N A
NA
Manuhova
L
L
Vorobjev
V S
VS
Sharonova
I N
IN
Skrebitsky
V G
VG
Victorov
I V
IV
Katchanov
J
J
Weih
M
M
Zorov
D B
DB
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D018929:Cell Culture Techniques; D015687:Cell Hypoxia / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D003022:Clotrimazole / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D000935:Antifungal Agents; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D003022:Clotrimazole; D005947:Glucose; D002118:Calcium