Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 50, Issue 10, Pages 1368-1381Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.02.021
Keywords
Cannabinoids; Oxidative stress; Inflammation; Ischemia/reperfusion; Free radicals
Funding
- NIH/NIAAA
- NIDA [9789]
- Hungarian Research Council [OTKA-NKTH-EU MB08-80238]
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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), mitochondria! dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-alpha), cyclooxygenase 2, macrophage inflammatory protein-1 alpha/2, intercellular adhesion molecule 1 mRNA levels: tissue neutrophil infiltration: nuclear factor kappa B (NF-kappa B) 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-kappa B activation and TNF-alpha production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-alpha 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. Published by Elsevier Inc.
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