The monoacylglycerol lipase inhibitorJZL184 attenuatesLPS‐induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action

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Abstract
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 ofJZL184 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 theCB1receptor antagonist,AM251 or theCB2receptor antagonist,AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels,MAGLactivity, 2‐AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen.Key results: JZL184 attenuatedLPS‐induced increases inIL‐1β,IL‐6,TNF‐α andIL‐10 but not the expression of the inhibitor ofNFkB(IκBα) in rat frontal cortex.AM251 attenuatedJZL184‐induced decreases in frontal corticalIL‐1β expression. Although arachidonic acid levels in the frontal cortex were reduced inJZL184‐treated rats,MAGLactivity, 2‐AG,PGE2andPGD2were unchanged. In comparison,MAGLactivity was inhibited and 2‐AGlevels enhanced in the spleen followingJZL184. In plasma,LPS‐induced increases inTNF‐α andIL‐10 levels were attenuated byJZL184, an effect partially blocked byAM251. In addition,AM630 blockedLPS‐induced increases in plasmaIL‐1β in the presence, but not absence, ofJZL184.Conclusion and implications: Inhibition of peripheralMAGLin rats byJZL184 suppressedLPS‐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 visithttp://dx.doi.org/10.1111/bph.2013.169.issue‐4&http://dx.doi.org/10.1111/bph.2012.167.issue‐8

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