A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury

Br J Pharmacol. 2012 Apr;165(8):2462-78. doi: 10.1111/j.1476-5381.2011.01381.x.

Abstract

Background and purpose: Cannabinoid CB(2) receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury.

Experimental approach: 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.

Key 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.

Conclusion and implications: HU-910 is a potent CB(2) receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.

Linked articles: 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alanine Transaminase / blood
  • Aldehydes / metabolism
  • Animals
  • Apoptosis / drug effects
  • Aspartate Aminotransferases / blood
  • Bridged Bicyclo Compounds / metabolism
  • Bridged Bicyclo Compounds / therapeutic use*
  • CHO Cells
  • Cell Death / drug effects
  • Cell Line
  • Cricetinae
  • Cytokines / genetics
  • DNA Fragmentation
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Protective Agents / metabolism
  • Protective Agents / therapeutic use*
  • RNA, Messenger / metabolism
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology

Substances

  • Aldehydes
  • Bridged Bicyclo Compounds
  • Cytokines
  • HU-910
  • Protective Agents
  • RNA, Messenger
  • Receptor, Cannabinoid, CB2
  • Intercellular Adhesion Molecule-1
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • 4-hydroxy-2-nonenal