Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia–reperfusion injury complicated by endotoxaemia

Background/Aim: Endotoxemia can complicate hepatic ischemia-reperfusion (IR) injury. Endocannabinoids appear to modulate the hemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxemia. Methods: Sprague-Dawley rats pre-treated with Rimonabant 3 or 10 mg/kg or vehicle underwent partial hepatic IR and LPS injection at reperfusion. Liver injury was evaluated by serum ALT and necrotic cell count. The inflammatory response was investigated by assessing the hepatic neutrophil infiltration, the TNF-α, IFN-γ, IL-6, SOCS1, and SOCS3 gene expression by RT-PCR. Systolic blood pressure and hepatic blood flow were measured as hemodynamic parameters. Finally, the lipid peroxidation, glutathione status, and immunoreactive CB1-receptor expression in the liver were also determined. Results: Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism. Rimonabant-treated rats showed a significant higher gene expression of IFN-γ, IL-6, SOCS1, and SOCS3 in the "early" reperfusion, while that of TNF-α was reduced. These findings were associated with an increased STAT3 phosphorylation. Furthermore, CB1-receptor antagonism significantly improved the oxidative injury and hemodynamic alterations occurring during reperfusion in untreated rats. Finally, CB1-receptor immunoreactivity was up-regulated early after reperfusion. Conclusions: This study firstly demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved.