Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy

Al Houayek, Mireille [UCL] Masquelier, Julien [UCL] Muccioli, Giulio [UCL]

The endocannabinoid system is implicated in, and regulates, several physiological processes, ranging from food intake and energy balance to pain and inflammation. 2-Arachidonoylglycerol (2-AG) is a full agonist at the cannabinoid receptors which classically mediate its effects. The activity of this bioactive lipid is dependent on its endogenous levels, which are tightly controlled by several hydrolases, monoacylglycerol lipase and a/b-hydrolase domain 6 and 12. Moreover, 2-AG is also a substrate of cyclooxygenase-2, and this reaction leads to the formation of prostaglandin glycerol esters, the effects of which remain to be fully elucidated. In this review we discuss the multiple mechanisms by which 2-AG controls inflammation and the therapeutic potential of 2-AG metabolism inhibitors. 2-Arachidonoylglycerol metabolism: where the endocannabinoid and the eicosanoid systems meet The endocannabinoid 2-arachidonoylglycerol (2-AG) is a bioactive lipid activating the CB1 and CB2 cannabinoid receptors, following on-demand production (Box 1). As for many bioactive lipids, the activity of 2-AG is controlled by its tissue levels, and therefore by the balance between its production and degradation. For years, 2-AG metabolism was considered to be straightforward. Its primary biosynthetic route consists of an activity-dependent phospholipase C-b (PLCb) that releases diacylglycerol (DAG) from phosphatidylinositol- 4,5-bisphosphate, which in turn is metabolized by diacylglycerol lipases (DAGLs) – with DAGLa and DAGLb having prevalent roles in the brain and in several peripheral tissues, respectively – to produce 2-AG [1–4]. 2-AG is then inactivated through hydrolysis into arachidonic acid by monoacylglycerol lipase (MAGL). It is now clear that this description is over simplistic. Several elements need to be considered to obtain a full picture of 2-AG metabolism [5]. For instance, although MAGL is the main enzyme controlling 2-AG levels in numerous tissues, two additional a/b hydrolases – a/b-hydrolase domain (ABHD)6 and ABHD12 – can similarly hydrolyze 2-AG [6–8]. Beside these hydrolases, recent reports