Δ8-Tetrahydrocannabivarin prevents hepatic ischaemiareperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors.
Activation of cannabinoid CB(2) receptors protects against various forms of ischaemia-reperfusion (IR) injury. Δ(8) -Tetrahydrocannabivarin (Δ(8) -THCV) is a synthetic analogue of the plant cannabinoid Δ(9) -tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB(2) receptors. Here, we assessed effects of Δ(8) -THCV and its metabolite 11-OH-Δ(8) -THCV on CB(2) receptors and against hepatic IR injury. Effects in vitro were measured with human CB(2) receptors expressed in CHO cells. Hepatic IR injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo. Displacement of (3) HCP55940 by Δ(8) -THCV or 11-OH-Δ(8) -THCV from specific binding sites in CHO cell membranes transfected with human CB(2) receptors (hCB(2) ) yielded K(i) values of 68.4 and 59.95 nM respectively. Δ(8) -THCV or 11-OH-Δ(8) -THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC(50) 12.95 and 14.3 nM respectively). Δ(8) -THCV, given before induction of IR, 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-α, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 37 activity and DNA fragmentation. Protective effects of Δ(8) -THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB(2) receptor antagonist attenuated the protective effects of Δ(8) -THCV, while a CB(1) antagonist tended to enhance it. Δ(8) -THCV activated CB(2) receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with IR partly via CB(2) receptor activation. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit httpdx.doi.org10.1111bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit httpdx.doi.org10.1111bph.2011.163.issue-7.