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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 10 OCT 25 2013.
• Citações Web of Science: 28

Resumo

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)

• Processo FAPESP: 11/10181-7 - "efeitos do 2-ag, através da inibição da monoacilglicerol lipase, em um modelo murino de inflamação pulmonar aguda induzida por lps"
• Beneficiário: Carolina Costola de Souza Pavani
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/51886-3 - Neuroimunomodulação: fármacos, estresse e citocinas nas relações entre os sistemas nervoso, endócrino e imune
• Beneficiário: João Palermo Neto
• Modalidade de apoio: Auxílio à Pesquisa - Temático