50. Inhibitors of monoacylglycerol lipase, URB602 and JZL184, decrease inflammation in a dose-dependent murine model of acute lung injury

Abstract

The endocannabinoids such as 2-AG modulate immune response. It is known that the levels of 2-AG are increased by monoacylglycerol lipase (MAGL) inhibition. The aim of this work was to investigate the effects of URB602 and JZL184 (MAGL inhibitors) in a murine model of lung injury. Fifty-nine C57BL/6 male mice were used URB602 treatment: mice were randomly divided into 6 groups ( n = 6–8), vehicle + saline, vehicle + LPS, and URB602 + LPS (10, 15, 20 or 25 mg/kg). JZL184 treatment: mice were randomly divided into 5 groups, vehicle + saline, vehicle + LPS, and JZL184 + LPS (4, 16 or 40 mg/kg). URB602 or JZL184 treatments were made (i.p.) 30 or 60 min before an intranasal instillation of LPS or sterile saline. Twenty-four hours later, mice were euthanized and bronchoalveolar lavage fluid (BAL) was harvested. Mice that received intranasal LPS presented more neutrophils in the BAL than mice that received intranasal saline. Animals treated with all doses of URB602 and JZL184 (16 and 40 mg/kg) presented a reduction in the number of inflammatory cells induced by LPS. No differences were found among the doses of URB602 used. Further analysis showed that JZL184 induced more relevant effects in the total number of cells and neutrophils in the BAL than URB602. The number of lymphocytes and macrophages were not changed by the drugs used. Altogether, present data show that increment on 2-AG induced by MAGL inhibition decrease LPS-induced lung inflammation in mice.