title: Carbamazepine promotes liver regeneration and survival in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Nawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D006498:Hepatectomy; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D002220:Carbamazepine; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: 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