Effect of monoacylglycerol lipase inhibition on intestinal permeability in chronic stress model

Jing Wang,Xiaohua Zhang,Chongmei Yang,Shulei Zhao

doi:10.1016/j.bbrc.2020.02.173

Jing Wang, Xiaohua Zhang + Show 2 more

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https://doi.org/10.1016/j.bbrc.2020.02.173

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Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). The present study aimed to explore the effects of inhibition of MAGL on intestinal permeability. We first tested it in differentiated CaCO2 cells after 21 days’ culture. The rat model of water avoidance stress (WAS) was established, and rats were divided into four groups according to intervention. Rats received intraperitoneal injection (i.p.) of an MAGL inhibitor (JZL184) alone, JZL184 and a the cannabinoid receptor 1 (CB1) receptor antagonist (SR141716A), JZL184 and a cannabinoid receptor 2 (CB2) receptor antagonist (AM630) or vehicle alone (control). We analyzed the fluorescein isothiocyanate-dextran (FD4) permeability and 2-AG level. Expression of MAGL and tight-junction-associated proteins were detected by western blot. Compared with the control group, MAGL expression was higher and 2-AG levels lower among WAS rats. Intestinal permeability was increased following administration of JZL184 which occurred due to up-regulation of tight-junction-associated proteins Claudin-1, Claudin-2, Claudin-5 and Occludin. The effects of MAGL inhibition were mediated by CB1, indicating that MAGL may represent a novel target for the treatment of reduced intestinal permeability in the context of chronic stress.

Highlights

The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL)
The effects of MAGL inhibition were mediated by cannabinoid receptor 1 (CB1), indicating that MAGL may represent a novel target for the treatment of reduced intestinal permeability in the context of chronic stress
Inhibition of monoacylglycerol lipase increased expression of tight-junction-associated proteins in vitro To test whether tight junction could be disrupted in human cells, differentiated Caco‐2 cells were treated with JZL184

Summary

Introduction

The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). The present study aimed to explore the effects of inhibition of MAGL on intestinal permeability. N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are two of the most important endocannabinoids in the human body. Tight junctions are multiprotein complexes made up of occludin, claudin-1–5, ZO-1, E-cadherin, etc., which play an important role in the formation and function of the mechanical barrier between epithelial cells. Tight junction proteins participate in the maintenance of the barrier function of the intestinal epithelium by regulating mucosal permeability[7]. It has been reported that the function of the intestinal epithelial barrier is compromised, possibly increasing intestinal permeability, in a variety of gastrointestinal dysfunction diseases including IBS[8]

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