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

Sandor Batkai, Partha Mukhopadhyay, Bela Horvath, Mohanraj Rajesh, Rachel Y. Gao, Anu Mahadevan, Mukkanti Amere, Natalia Battista, Aron H. Lichtman, Lisa A. Gauson, Mauro Maccarrone, Roger G. Pertwee, Pal Pacher*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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 [H-3]CP55940 by Delta(8)-THCV or 11-OH-Delta(8)-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB(2)) yielded K-i values of 68.4 and 59.95 nM respectively. Delta(8)-THCV or 11-OH-Delta(8)-THCV inhibited forskolin-stimulated cAMP production by hCB(2) 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.

Original languageEnglish
Pages (from-to)2450-2461
Number of pages12
JournalBritish Journal of Pharmacology
Volume165
Issue number8
Early online date23 Mar 2012
DOIs
Publication statusPublished - Apr 2012

Keywords

  • cannabinoids
  • oxidative stress
  • inflammation
  • ischaemia-reperfusion
  • ISCHEMIA-REPERFUSION INJURY
  • NITRIC-OXIDE
  • CELL-DEATH
  • IN-VIVO
  • ISCHEMIA/REPERFUSION INJURY
  • DIABETIC CARDIOMYOPATHY
  • DELTA(9)-TETRAHYDROCANNABIVARIN
  • PEROXYNITRITE
  • DYSFUNCTION
  • PROTECTS

Cite this

Batkai, S., Mukhopadhyay, P., Horvath, B., Rajesh, M., Gao, R. Y., Mahadevan, A., Amere, M., Battista, N., Lichtman, A. H., Gauson, L. A., Maccarrone, M., Pertwee, R. G., & Pacher, P. (2012). Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. British Journal of Pharmacology, 165(8), 2450-2461. https://doi.org/10.1111/j.1476-5381.2011.01410.x