161. Effects of MAGL inhibition and the CB1 and CB2 cannabinoids receptors participation in the neutrophils recruitment and activity in a murine model of acute lung injury induced by LPS

Abstract

Endocannabinoid signaling is terminated by enzymatic hydrolysis; process that 2-Arachidonoylglycerol (2-AG) is mediated by monoacylglycerol lipase (MAGL). The MAGL inhibition increases 2-AG levels, an endocannabinoid that acts on CB1 and CB2 receptors. In inflammation, the neutrophils are the first leukocytes to migrate to the injury focus. The aim was to investigate the effects of MAGL inhibition (with JZL184) in the neutrophils recruitment and activity in a murine model of acute lung injury (ALI) induced by LPS. Fifty C57BL/6 male mice were used (5–10/group) and divided into vehicle + saline, vehicle + LPS, and JZL184 + LPS groups. Mice were treated with JZL184 (16 mg/kg) or vehicle and after 60 min they received a LPS intranasal instillation (100 μg/ mL; 1 μL/g) or saline. Six, 24 and 48 h later mice were euthanized and bronchoalveolar lavage fluid and lungs were harvested to KC, MIP-2 and MPO analysis. The LPS was able to increase the KC, MIP-2 and MPO levels and the JZL184 treatment prevented all these parameters. The treatment with AM281 and AM230 (CB1 and CB2 antagonists, respectively), administered i.p. (2,5 and/or 5 mg/kg) 30 min before JZL184 treatment, showed that antagonists prevented the JZL184 anti-inflammatory effects. ALI establishment was evident 6, 24 and 48 h after LPS intranasal instillation and the MAGL inhibition has anti-inflammatory effects. CB1 and CB2 receptors were connected with JZL184 anti-inflammatory effects in ALI murine model. FAPESP2011/10181-7;2009/51886-3.