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

Sándor Bátkai, Partha Mukhopadhyay, Bela Horváth, Mohanraj Rajesh, Rachel Y. Gao, Anu Mahadevan, Mukkanti Amere, Natalia Battista, Aron H. Lichtman, Lisa A. Gauson, Mauro Maccarrone, Roger G. Pertwee, Pál Pacher

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2450-2461
Number of pages12
JournalBritish Journal of Pharmacology
Volume165
Issue number8
DOIs
Publication statusPublished - Apr 2012

Keywords

  • Cannabinoids
  • Inflammation
  • Ischaemia-reperfusion
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Δ 8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB 2 receptors'. Together they form a unique fingerprint.

Cite this