BACKGROUND & AIMS: Carbamazepine (CBZ), a widely used anticonvulsant and mood stabilizer, activates multiple proliferative and pro-survival pathways. Here, we hypothesize that CBZ may promote hepatocellular proliferation and ameliorate liver regeneration. METHODS: C57BL6/J mice were orally administered CBZ or vehicle and underwent a 70% partial hepatectomy (PHx), 85% PHx or treatment with carbon tetrachloride (CCl4). Liver regeneration was determined by liver to body weight ratio, hepatocyte proliferation markers, and activation of intracellular signalling pathways. RESULTS: Two to 5days after the 70% PHx, the liver to body weight ratio was significantly higher in the CBZ-treated mice than in the vehicle-treated mice. CBZ treatment upregulated the number of proliferative hepatocytes following PHx or CCl4 treatment, as assessed by intrahepatic Ki-67 staining, BrdU uptake, and PCNA protein expression. PHx surgery induced the expression of several cyclins and activated Akt/mTOR signalling pathways, all of which were enhanced by CBZ treatment. The administration of the mTOR inhibitor temsirolimus abrogated the hepato-proliferative effect of CBZ. CBZ treatment significantly improved the survival rate of the mice that underwent lethal 85% massive hepatectomy. CONCLUSIONS: CBZ demonstrated a novel hepato-proliferative effect through the activation of the mTOR signalling pathway in hepatectomised mice. CBZ has the potential to be a therapeutic option for facilitating efficient liver regeneration in patients subjected to liver surgery.
BACKGROUND & AIMS:Carbamazepine (CBZ), a widely used anticonvulsant and mood stabilizer, activates multiple proliferative and pro-survival pathways. Here, we hypothesize that CBZ may promote hepatocellular proliferation and ameliorate liver regeneration. METHODS: C57BL6/J mice were orally administered CBZ or vehicle and underwent a 70% partial hepatectomy (PHx), 85% PHx or treatment with carbon tetrachloride (CCl4). Liver regeneration was determined by liver to body weight ratio, hepatocyte proliferation markers, and activation of intracellular signalling pathways. RESULTS: Two to 5days after the 70% PHx, the liver to body weight ratio was significantly higher in the CBZ-treated mice than in the vehicle-treated mice. CBZ treatment upregulated the number of proliferative hepatocytes following PHx or CCl4 treatment, as assessed by intrahepatic Ki-67 staining, BrdU uptake, and PCNA protein expression. PHx surgery induced the expression of several cyclins and activated Akt/mTOR signalling pathways, all of which were enhanced by CBZ treatment. The administration of the mTOR inhibitor temsirolimus abrogated the hepato-proliferative effect of CBZ. CBZ treatment significantly improved the survival rate of the mice that underwent lethal 85% massive hepatectomy. CONCLUSIONS:CBZ demonstrated a novel hepato-proliferative effect through the activation of the mTOR signalling pathway in hepatectomised mice. CBZ has the potential to be a therapeutic option for facilitating efficient liver regeneration in patients subjected to liver surgery.