Cannabinoid 2 receptor modulation in experimental sepsis

Introduction: Sepsis results from a dysregulated immune response to an infection. Current medical treatments are of limited efficacy with regard to improvement of survival. The endocannabinoid system (ECS) opens a novel avenue in sepsis therapy due to its unique characteristics. Cannabinoid 2 (CB2) receptors are expressed on the surface of all immune cells, providing a direct approach to the modulation of the immune system. The present study explored the effects of CB2 receptor modulation in a mouse model of acute sepsis (endotoxemia). Methods: The treatment compounds tested were: a specific CB2 receptor agonist, HU308, a CB2 receptor antagonist/inverse agonist, AM630, and the cannabinoid degradation enzyme inhibitors URB597 (fatty acid amide hydrolase inhibitor), and JZL184 (monoacylglycerol lipase inhibitor). Resuts: Administration of the CB2 receptor agonist, HU308, reduced significantly the number of adhering leukocytes in submucosal venules, but did not restore muscular and mucosal villi FCD in endotoxemic mice. The CB2 receptor antagonist, AM630, did not exacerbate leukocyte activation within the intestinal microcirculation, but further reduced muscular and mucosal FCD oft he intestinal wall. The cannabinoid degradation enzyme inhibitors URB597 and JZL184 both significantly reduced the number of adhering leukocytes in submucosal venules. Furthermore, JZL184 administration completely restored muscular FCD. Conclusions: CB2 receptor activation by a specific agonist or cannabinoid degradation enzyme inhibition was effective in reduction of leukocyte activation within the intestinal microcirculation. The CB2 receptor pathway seems to be involved in the inflammatory cascade elicited early during sepsis. Therefore, modulation of the CB2 receptor pathway might offer new therapeutic options for the manipulation of the immune system in sepsis.