Anti-apoptotic pro-survival effect of clotrimazole in a normothermic ischemia reperfusion injury animal model.
BACKGROUND
Increasing evidence suggests that apoptosis plays a critical role in ischemia reperfusion (IR)-mediated liver injury. Clotrimazole (CTZ) is a potent antimycotic drug that also has a free radical scavenger activity. This study investigated the possible anti-apoptotic, pro-survival role of CTZ in hepatic IR injury in rats.


METHODS
Male Sprague-Dawley rats were divided into three groups: sham, control, and CTZ-treated (n = 10 each). Control and CTZ-treated animals were subjected to 60 min of normothermic ischemia of the left lateral lobe of the liver followed by 6 h of reperfusion. Animals were then sacrificed, the liver excised, and blood samples collected.


RESULTS
CTZ induced a significant increase in expression of anti-apoptotic Bcl-xL protein. Serum levels of aspartate transaminase and alanine transaminase were significantly lower in CTZ-treated animals than in controls. Histopathologically, tissue damage in the form of apoptosis was significantly lower in CTZ-treated animals than in controls. Expression of the activated form of caspase-3 and the cleaved form of its substrate, poly-ADP-ribose polymerase, decreased significantly in the CTZ-treated group compared with controls. CTZ increased the expression of phospho-p 44/42 ERK1/2 and decreased the phosphorylated form of JNK, without affecting p38 MAPK.


CONCLUSIONS
CTZ protects the liver against IR apoptosis in rats through overexpression of the anti-apoptotic protein Bcl-xL. Other pro-survival pathways such as phospho-p 44/42 ERK1/2 kinase are also activated while JNK is down-regulated.
Iannelli
Antonio
A
Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet 2, Nice, France. antonio_iannelli@hotmail.com
de Sousa
George
G
Zucchini
Nathalie
N
Saint-Paul
Marie Christine
MC
Gugenheim
Jean
J
Rahmani
Roger
R
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003022:Clotrimazole / Q000494:pharmacology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013696:Temperature; D051020:bcl-X Protein / Q000378:metabolism
D000935:Antifungal Agents; C494813:Bcl2l1 protein, rat; D016166:Free Radical Scavengers; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051020:bcl-X Protein; D003022:Clotrimazole