Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors
Article first published online: 23 MAR 2012
Published 2011. This article is a U.S. Government work and is in the public domain in the USA.
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2450–2461, April 2012
How to Cite
Bátkai, S., Mukhopadhyay, P., Horváth, B., Rajesh, M., Gao, R. Y., Mahadevan, A., Amere, M., Battista, N., Lichtman, A. H., Gauson, L. A., Maccarrone, M., Pertwee, R. G. and Pacher, P. (2012), Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. British Journal of Pharmacology, 165: 2450–2461. doi: 10.1111/j.1476-5381.2011.01410.x
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 6 APR 2011 08:37AM EST
- Received; 24 November 2010; Revised; 14 February 2011; Accepted; 10 March 2011
- oxidative stress;
BACKGROUND AND PURPOSE Activation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Δ8-Tetrahydrocannabivarin (Δ8-THCV) is a synthetic analogue of the plant cannabinoid Δ9-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of Δ8-THCV and its metabolite 11-OH-Δ8-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 Δ8-THCV or 11-OH-Δ8-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. Δ8-THCV or 11-OH-Δ8-THCV inhibited forskolin-stimulated cAMP production by hCB2 CHO cells (EC50= 12.95 and 14.3 nM respectively). Δ8-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 Δ8-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 Δ8-THCV, while a CB1 antagonist tended to enhance it.
CONCLUSIONS AND IMPLICATIONS Δ8-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