title: A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury.
abstract: OBJECTIVE
  Cannabinoid CB(2) receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury.
  
  
  METHODS
  We have investigated the effects of a novel CB(2) receptor agonist ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol (HU-910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well-established mouse model of segmental hepatic I/R.
  
  
  RESULTS
  Displacement of [(3) H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB(2) or CB(1) receptors (hCB(1/2) ) yielded K(i) values of 6 nM and 1.4 µM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC(50) = 162 nM) and yielded EC(50) of 26.4 nM in [(35) S]GTPγS binding assays using hCB(2) expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic pro-inflammatory chemokines (CCL3 and CXCL2), TNF-α, inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB(2) receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB(1) antagonist tended to enhance them.
  
  
  CONCLUSIONS
  HU-910 is a potent CB(2) receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors: Laboratory of Physiologic Studies Liver Disease, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
authors: Bėla
authors: B
authors: Horváth
authors: Lital
authors: L
authors: Magid
authors: Partha
authors: P
authors: Mukhopadhyay
authors: Sándor
authors: S
authors: Bátkai
authors: Mohanraj
authors: M
authors: Rajesh
authors: Ogyi
authors: O
authors: Park
authors: Galin
authors: G
authors: Tanchian
authors: Rachel Y
authors: RY
authors: Gao
authors: Catherine E
authors: CE
authors: Goodfellow
authors: Michelle
authors: M
authors: Glass
authors: Raphael
authors: R
authors: Mechoulam
authors: Pál
authors: P
authors: Pacher
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000627:therapeutic use*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics; D053938:DNA Fragmentation; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000447:Aldehydes; D001643:Bridged Bicyclo Compounds; D016207:Cytokines; C573862:HU-910; D020011:Protective Agents; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D018799:Intercellular Adhesion Molecule-1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C027576:4-hydroxy-2-nonenal