Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice

Author(s)

Costola-de-Souza, Carolina ^[1] ; Ribeiro, Alison ^[1] ; Ferraz-de-Paula, Viviane ^[2] ; Calefi, Atilio Sersun ^[1] ; Arrais Aloia, Thiago Pinheiro ^[1] ; Gimenes-Junior, Joao Antonio ^[3] ; de Almeida, Vinicius Izidio ^[1] ; Pinheiro, Milena Lobao ^[1] ; Palermo-Neto, Joao ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Vet Med, Dept Pathol, Neuroimmunomodulat Res Grp, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Expt Toxicol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS One; v. 8, n. 10 OCT 25 2013.
• Web of Science Citations: 28

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-4morpholinyl- 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. (AU)

• FAPESP's process: 11/10181-7 - "EFFECTS OF 2-AG, THROUGH MONOACYLGLYCEROL LIPASE INHIBITION, IN A MURINE MODEL OF ACUTE LUNG INJURY LPS-INDUCED"
• Grantee: Carolina Costola de Souza Pavani
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 09/51886-3 - Neuroimmunomodulation: drugs, stress and cytokines on nervous, endocrine and immune systems relationships
• Grantee: João Palermo Neto
• Support Opportunities: Research Projects - Thematic Grants