hu-308 and Ischemia

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.

Topics: Alanine Transaminase; Animals; Apoptosis; Cannabinoid Receptor Agonists; Cannabinoids; Cell Adhesion; Chemokines; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Ischemia; L-Lactate Dehydrogenase; Leukocytes; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Peroxidase; Reperfusion Injury; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Cannabinoids; Endocannabinoids; Inflammation; Ischemia; Ligands; Mice; Receptors, Cannabinoid; Reperfusion Injury