title: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis.
abstract: In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
authors.affiliation: Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Douglas
authors.initials: D
authors.lastname: Osei-Hyiaman
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D018925:Chemokines / Q000097:blood; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D018925:Chemokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C402416:HU 308; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D000410:Alanine Transaminase