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

• Published in: British journal of pharmacology Vol. 165; no. 8; pp. 2462 - 2478
• Main Authors: Horváth, Bėla, Magid, Lital, Mukhopadhyay, Partha, Bátkai, Sándor, Rajesh, Mohanraj, Park, Ogyi, Tanchian, Galin, Gao, Rachel Y, Goodfellow, Catherine E, Glass, Michelle, Mechoulam, Raphael, Pacher, Pál
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2012
• Subjects: Alanine Transaminase - blood; Aldehydes - metabolism; Animals; Apoptosis - drug effects; Aspartate Aminotransferases - blood; Bridged Bicyclo Compounds - metabolism; Bridged Bicyclo Compounds - therapeutic use; cannabinoids; Cell Death - drug effects; Cell Line; CHO Cells; Cricetinae; Cytokines - genetics; DNA Fragmentation; Humans; inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Intercellular Adhesion Molecule-1 - genetics; ischaemia‐reperfusion; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; oxidative stress; Oxidative Stress - drug effects; Protective Agents - metabolism; Protective Agents - therapeutic use; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; RNA, Messenger - metabolism; Themed Section: Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01381.x

BACKGROUND AND PURPOSE Cannabinoid CB2 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 CB2 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 [3H]CP55940 by HU‐910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB1/2) yielded Ki values of 6 nM and 1.4 µM respectively. HU‐910 inhibited forskolin‐stimulated cyclic AMP production by hCB2 CHO cells (EC50= 162 nM) and yielded EC50 of 26.4 nM in [35S]GTPγS binding assays using hCB2 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 CB2 receptor antagonist attenuated the protective effects of HU‐910, while pretreatment with a CB1 antagonist tended to enhance them.
CONCLUSION AND IMPLICATIONS HU‐910 is a potent CB2 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