title: Monoacylglycerol lipase (MAGL) inhibition attenuates acute lung injury in mice.
abstract: Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy) methyl) piperidine- 1-carboxylate (JZL184), is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p.)) of JZL184, in a murine model of lipopolysaccharide (LPS) -induced acute lung injury (ALI) 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL) and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone) blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.
authors.affiliation: Neuroimmunomodulation research group, Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Costola-de-Souza
authors.forename: Alison
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Viviane
authors.initials: V
authors.lastname: Ferraz-de-Paula
authors.forename: Atilio Sersun
authors.initials: AS
authors.lastname: Calefi
authors.forename: Thiago Pinheiro Arrais
authors.initials: TP
authors.lastname: Aloia
authors.forename: João Antonio
authors.initials: JA
authors.lastname: Gimenes-Júnior
authors.forename: Vinicius Izidio
authors.initials: VI
authors.lastname: de Almeida
authors.forename: Milena Lobão
authors.initials: ML
authors.lastname: Pinheiro
authors.forename: João
authors.initials: J
authors.lastname: Palermo-Neto
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D002199:Capillary Permeability / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D007211:Indoles; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D015815:Cell Adhesion Molecules; D063388:Endocannabinoids; D005989:Glycerides; D007211:Indoles; C534333:JZL 184; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C094023:iodopravadoline