Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.

Abstract

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.

• Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Béla Horváth, Sándor Bátkai, Ogyi Park, Galin Tanchian, Rachel Y Gao, Vivek Patel, David A Wink, Lucas Liaudet, György Haskó, Raphael Mechoulam, Pál Pacher
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 50 Issue 10 Pg. 1368-81 (May 15 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21362471 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Cannabidiol

Topics

• Animals
• Cannabidiol (pharmacology)
• Cell Death (drug effects)
• Disease Models, Animal
• Inflammation (metabolism)
• Liver (blood supply, cytology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress (drug effects)
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction (drug effects)