Cannabis and aspirin have been used for millennia to treat a

Cannabis and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. possess uncovered the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems collectively through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor swimming pools for pro-inflammatory eicosanoid synthesis in specific cells. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive anxiolytic and anti-emetic reactions and attenuate precipitated withdrawal symptoms in habit paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through decreasing eicosanoid production. In malignancy MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network but also by controlling fatty acid launch for the synthesis of protumorigenic signaling lipids. Therefore MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the varied (patho)physiological functions of MAGL and the restorative potential of MAGL inhibitors in treating a vast array of complex human diseases. efficacious inhibitors such as JZL184 as well as the development of MAGL-deficient (?/?) mice (Chanda et al. 2010 Long et al. TAK-779 2009 Schlosburg et al. 2010 Pharmacological or genetic inactivation of MAGL lowers 2-AG hydrolytic activity by >80 % in most cells including the mind while the remaining 20 % of 2-AG hydrolytic activity in mind arises from the uncharacterized serine hydrolases alpha/beta hydrolase website 6 (ABHD6) and ABHD12 (Blankman et al. VCL 2007 Dinh et al. TAK-779 2004 TAK-779 Although ABHD6 and ABHD12 may have functions in 2-AG hydrolysis in certain settings both genetic and pharmacological inactivation of MAGL lead to dramatic elevations in both bulk levels and depolarization-induced interstitial levels of 2-AG in the brain confirming that MAGL is indeed the primary enzyme involved in degrading 2-AG (Long et al. 2009 Nomura et al. 2011 Schlosburg et al. 2010 MAGL blockade shows tissue-specific variations in monoacylglycerol rate of metabolism with the brain showing the most dramatic elevations in 2-AG and peripheral cells often showing higher changes in additional monoacylglycerols consistent with the lipolytic part of MAGL as the final step of triglyceride hydrolysis in peripheral cells (Long et al. 2009 The endocannabinoid 2-AG is definitely thought to TAK-779 be created through hydrolysis of phospholipids by phospholipase C (PLC) β or δ to release diacylglycerols (DAG) and then degradation of DAG by diacylglycerol lipase (DAGL) α or β (Gao et al. 2010 Tanimura et al. 2010 Although the involvement of PLCs in DAG and 2-AG synthesis is not yet fully elucidated the creation of DAGL α and β-deficient mice offers cemented the functions of these enzymes in 2-AG synthesis and endocannabinoid function. Studies have shown that DAGL α is the main enzyme in mind and spinal cord whereas DAGL β takes on a primary part in the liver with modest functions in the brain for 2-AG synthesis (Gao et al. 2010 Tanimura et al. 2010 In addition to the part of MAGL in terminating 2-AG signaling we have recently found that MAGL releases AA the precursor for pro-inflammatory prostaglandin synthesis in certain cells. MAGL blockade lowers bulk AA levels in the brain stoichiometrically to 2-AG elevation which also results in a reduction of lipopolysaccharide (LPS)-induced pro-inflammatory levels of downstream COX-driven prostaglandin and thromboxane production in the brain (Nomura et al. TAK-779 2011 These results were quite amazing since phospholipases have been considered to be the dominating AA-releasing enzyme for prostaglandin production (Buczynski et al. 2009 Instead there is an anatomical demarcation in enzymes that regulate this process in which MAGL takes on this part not only in the brain but also in the liver and lung whereas cytosolic phospholipase A2 (cPLA2) is the dominating AA-releasing enzyme in gut spleen and macrophages (Bonventre et al. 1997 Nomura et al. 2011 Recently Jaworski et al. showed that adipose-specific PLA2 (AdPLA2) settings.