[Delta]8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors

BACKGROUND AND PURPOSE Activation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. [Delta]8-Tetrahydrocannabivarin ([Delta]8-THCV) is a synthetic analogue of the plant cannabinoid [Delta]9-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of [Delta]8-THCV and its metabolite 11-OH-[Delta]8-THCV on CB2 receptors and against hepatic I/R injury. EXPERIMENTAL APPROACH Effects in vitro were measured with human CB2 receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo. KEY RESULTS Displacement of [3H]CP55940 by [Delta]8-THCV or 11-OH-[Delta]8-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB2) yielded Ki values of 68.4 and 59.95 nM respectively. [Delta]8-THCV or 11-OH-[Delta]8-THCV inhibited forskolin-stimulated cAMP production by hCB2 CHO cells (EC50= 12.95 and 14.3 nM respectively). [Delta]8-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2,TNF-[alpha], intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of [Delta]8-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of [Delta]8-THCV, while a CB1 antagonist tended to enhance it. CONCLUSIONS AND IMPLICATIONS [Delta]8-THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB2 receptor activation. 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 ABSTRACT]