A new cannabinoid CB ₂receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury

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 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 CB ₂or 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 [ ³⁵S]GTPγS binding assays using hCB ₂expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory 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.