title: Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on focal cerebral ischemia/reperfusion-induced inflammation, oxidative stress, and apoptosis in rats.
abstract: OBJECTIVE
  Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains.
  
  
  METHODS
  Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains.
  
  
  RESULTS
  Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration.
  
  
  CONCLUSIONS
  GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.
authors.affiliation: Department of Anaesthesiology, General Hospital of the People's Liberation Army, Chengdu, Sichuan, China.
authors.forename: Gu
authors.initials: G
authors.lastname: Gong
authors.affiliation: Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Libang
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Anaesthesiology, General Hospital of the People's Liberation Army, Chengdu, Sichuan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Anaesthesiology, General Hospital of the People's Liberation Army, Chengdu, Sichuan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Anaesthesiology, General Hospital of the People's Liberation Army, Chengdu, Sichuan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Anaesthesiology, General Hospital of the People's Liberation Army, Chengdu, Sichuan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D019695:Glycyrrhizic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D024243:HMGB1 Protein; D018696:Neuroprotective Agents; D019695:Glycyrrhizic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases