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

Abstract

BACKGROUND AND PURPOSECannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury. EXPERIMENTAL APPROACHWe 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 [ 3 H]CP55940by 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 mM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB2 CHO cells (EC50 = 162 nM) and yielded EC50 of 26.4 nM in [ 35 S]GTPgS binding assays using hCB2 expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-a, 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-a production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-a. 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 IMPLICATIONSHU-910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. Abbreviations 4-HNE, 4-hydroxy-2-nonenal (marker of lipid peroxidation); CB2 or CB1 receptor, cannabinoid 1 or 2 receptor; HU-910, ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol; I/R, ischaemia/reperfusion; ICAM-1, inter-cellular adhesion molecule 1, CD54;CCL2, monocyte chemotactic protein-1; CCL3, macrophage inflammatory protein-1a; CXCL2, macrophage inflammatory protein-2a; VCAM-1, vascular cell adhesion molecule 1 LINKED ARTICLES

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