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.
Highlights
The discovery of the CB1 and CB2 cannabinoid receptors and their major ligands N-arachidonoylethanolamide and 2-arachidonoylglycerol (2-AG) led to the characterization of the endocannabinoid system [1][2][3][4]
No differences were found in mice that received intranasal saline, whether they were treated (E1) or not (C1) with JZL184, i.e., JZL184 induced no effects in the absence of LPS-induced acute lung injury (ALI)
We investigated the effects of monoacylglycerol lipase (MAGL) inhibition (JZL184 16 mg/kg) on leukocyte migration into the murine lungs at 6, 24 and 48 hours after the LPS-induced ALI
Summary
The discovery of the CB1 and CB2 cannabinoid receptors and their major ligands N-arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) led to the characterization of the endocannabinoid system [1][2][3][4] This system has become a subject of great interest in pharmacology due to its remarkable distribution in mammals and its capacity to play a modulating role in diverse physiological functions including immunomodulation and inflammation [5]. JZL184 has been shown to have potent immunosuppressive and anti-inflammatory properties in some rodent models of inflammation [9][10] Employing this drug (16 mg/kg, given systemically), a remarkable variety of CB1dependent effects such as analgesia, hypomotility and hypothermia were shown in mice [7]. Using JZL184 (8 mg/kg i.p.), Busquets-Garcia et al (2011) [11] highlighted the anxiolytic effects of this drug in mice and suggested that the observed effects might have been induced by 2-AG actions on the CB2 receptors; an antinociceptive effect related to the CB1 and the CB2 receptor activation has been reported in mice [11]
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