Carbamazepine promotes liver regeneration and survival in mice

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.

Akt; CBZ; CCl(4); Carbamazepine; DMSO; ERK; H&E; HGF; Hepatocyte proliferation; IHC; JNK; Liver regeneration; MAPK; NPC; PHx; PI-3K; RT-PCR; c-jun N-terminal kinase; carbamazepine; carbon tetrachloride; dimethyl sulfoxide; extracellular signal regulated kinase; haematoxylin and eosin; hepatocyte growth factor; immunohistochemistry; mTOR; non-parenchymal cells; partial hepatectomy; phosphotidylinositol-3 kinase; ras-mitogen-activated protein kinase; reverse transcription PCR.