The monoacylglycerol lipase inhibitor jzl184 attenuates lps-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action

Background and purpose JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. Experimental approach JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2receptor antagonist, AM630 were administered to rats 30min before lipopolysaccharide (LPS). 2h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. Key results JZL184 attenuated LPS-induced increases in IL-1, IL-6, TNF- and IL-10 but not the expression of the inhibitor of NFkB (IB) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1 expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF- and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1 in the presence, but not absence, of JZL184. Conclusion and implications Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-

The monoacylglycerol lipase inhibitor jzl184 attenuates lps-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action

Background and purpose JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. Experimental approach JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2receptor antagonist, AM630 were administered to rats 30min before lipopolysaccharide (LPS). 2h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. Key results JZL184 attenuated LPS-induced increases in IL-1, IL-6, TNF- and IL-10 but not the expression of the inhibitor of NFkB (IB) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1 expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF- and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1 in the presence, but not absence, of JZL184. Conclusion and implications Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-

The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management and metabolic diseases. However, around 2007 the tide began to turn when several cannabinoid receptor type 1 (CB1) antagonists/inverse agonists failed as therapeutics against overweight and its complications. More recently, the development of FAAH (Fatty Acid Amide Hydrolase) inhibitors against pain has also faced serious setbacks. In retrospect the much greater complexity of the ECS than originally assumed has played a fundamental role in these difficulties. Although there is no doubt that endocannabinoids and their receptors are of great (patho-)physiological relevance, it has become clear that the ECS is intimately intertwined with other biological systems. Endocannabinoids exist in equilibrium with fatty acids and their metabolic derivatives, including eicosanoids and prostamides. Furthermore, there are several biologically active analogues of endocannabinoids, in particular fatty acid amides, with metabolic pathways overlapping those of the ECS. Finally, endocannabinoids per se and their congeners show “promiscuous” behaviour going beyond interactions with CB1 and CB2 receptors. It has become clear that the complexity of what may be called the “endocannabinoidome” demands for pharmacological approaches that take into account these dynamics. Targeting the “endocannabinoidome” continues to offer opportunities for prevention and therapy, in particular for chronic diseases. However, chances for success are more likely to come from “multiple-target” than from “single-target” approaches