title: 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.affiliation: Laboratory of Physiologic Studies, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Galin
authors.initials: G
authors.lastname: Tanchian
authors.forename: Rachel Y
authors.initials: RY
authors.lastname: Gao
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002185:Cannabidiol