Br J Pharmacol. 2011 Mar 30. [Epub ahead of print]
A new cannabinoid 2 receptor agonist HU-910 attenuates oxidative stress, inflammation, and cell death associated with hepatic ischemia/reperfusion injury.
Horváth B, Magid L, Mukhopadhyay P, Bátkai S, Rajesh M, Park O, Tanchian G, Gao RY, Goodfellow CE, Glass M, Mechoulam R, Pacher P.
Laboratory of Physiologic Studies and Liver Disease, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA Institute of Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 92019, New Zealand.
Abstract
BACKGROUND AND PURPOSE: Cannabinoid 2 (CB(2) ) receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischemia-reperfusion (I/R) injury.
EXPERIMENTAL APPROACH: We have investigated the effects of a novel CB(2) receptor agonist HU-910 on liver injury inflicted by 1hour of ischemia followed by 2,6 or 24hours of reperfusion, using a well-established mouse model of segmental hepatic I/R.
KEY RESULTS: Displacement of [(3) H]CP55940 by HU-910 from specific binding sites in Chinese hamster ovary (CHO) cell membranes transfected with human CB(2) or CB(1) receptors (hCB(1/2) ) yielded Ki values of 6 nM and 1.4 µM, respectively. HU-910 inhibited the forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC(50) = 162 nM) and yielded EC(50) of 26.4 nM in [(35) S]GTP?S binding assay using hCB(2 ) expressing CHO membranes. HU-910 given prior to ischemia significantly attenuated the levels of I/R-induced hepatic pro-inflammatory chemokines (macrophage inflammatory protein-1a/2, monocyte chemotactic protein-1), cytokine tumor necrosis factor-a (TNF-a), and inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1h after the ischemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-a production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-a. CB2 receptor antagonist pretreatment significantly attenuated the protective effect of HU-910, while CB1 antagonist rather tended to enhance it.
CONCLUSIONS AND IMPLICATIONS: HU-910 is a potent CB(2) receptors agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. |
