Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors.
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
Previous studies have suggested that increased levels of endocannabinoids in various cardiovascular disorders (e.g. different forms of shock, cardiomyopathies, atherosclerosis) through the activation of CB1 cannabinoid receptors may promote cardiovascular dysfunction and tissue injury. We have investigated the role of the main endocannabinoid anandamide metabolizing enzyme (fatty acid amide hydrolase; FAAH) in the myocardial injury induced by an important chemotherapeutic drug doxorubicin (DOX; known for its cardiotoxicity mediated by increased reactive oxygen and nitrogen species generation) using well-established acute and chronic cardiomyopathy models in mice. The DOX-induced myocardial oxidative/nitrative stress (increased 4-hydroxynonenal(HNE), protein carbonyl, nitrotyrosine levels, decreased glutathione content) correlated with multiple cell death markers, which were enhanced in FAAH knockout mice exhibiting significantly increased DOX-induced mortality and cardiac dysfunction compared to their wild types. The effects of DOX in FAAH knockouts were attenuated by CB1 receptor antagonists. Furthermore, anandamide induced enhanced cell death in human cardiomyocytes pretreated by FAAH inhibitor, and enhanced sensitivity to ROS generation in inflammatory cells of FAAH knockouts. These results suggest that in pathological conditions associated with acute oxidative/nitrative stress FAAH plays a key role in controlling the tissue injury, which is, at least in part, mediated by the activation of CB1 receptors by endocannabinoids.
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