Cannabidiol Protects Against Hepatic Ischemia/reperfusion Injury by Attenuating Inflammatory Signaling and Response, Oxidative/nitrative Stress, and Cell Death

Overview

Journal Free Radic Biol Med

Specialties Biochemistry
Biology
General Medicine

Date 2011 Mar 3

PMID 21362471

Citations 94

Authors

Partha Mukhopadhyay

Mohanraj Rajesh

Bela Horvath

Sandor Batkai

Ogyi Park

Galin Tanchian

Rachel Y Gao

Vivek Patel

David A Wink

Lucas Liaudet

Gyorgy Hasko

Raphael Mechoulam

Pal Pacher

Affiliations

Soon will be listed here.

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.

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