Kerr_2013_Br.J.Pharmacol_169_808

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 CB2 receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h 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-1beta, IL-6, TNF-alpha and IL-10 but not the expression of the inhibitor of NFkB (IkappaBalpha) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1beta 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-alpha and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1beta 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-8.