Δ ⁸-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB ₂ receptors

BACKGROUND AND PURPOSE: Activation of cannabinoid CB ₂ receptors protects against various forms of ischaemia-reperfusion (I/R) 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 I/R injury. EXPERIMENTAL APPROACH: Effects in vitro were measured with human CB ₂ 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 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 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-α, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 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. CONCLUSIONS AND IMPLICATIONS: Δ ⁸-THCV activated CB ₂ receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB ₂ 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.