Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Rd, Jinan, 250021, China.
Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Rd, Jinan, 250021, China.
Biochem Biophys Res Commun. 2020 May 14;525(4):962-967. doi: 10.1016/j.bbrc.2020.02.173. Epub 2020 Mar 12.
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.
内源性大麻素 2-花生四烯酰甘油（2-AG）是一种抗伤害感受脂质，通过细胞摄取和随后的单酰基甘油脂肪酶（MAGL）代谢失活。本研究旨在探讨抑制 MAGL 对肠道通透性的影响。我们首先在培养 21 天后的分化 CaCO2 细胞中进行了测试。建立了大鼠回避应激（WAS）模型，并根据干预将大鼠分为四组。大鼠接受腹腔注射（i.p.）单独的 MAGL 抑制剂（JZL184）、JZL184 和大麻素受体 1（CB1）受体拮抗剂（SR141716A）、JZL184 和大麻素受体 2（CB2）受体拮抗剂（AM630）或单独的载体（对照）。我们分析了荧光素异硫氰酸酯-葡聚糖（FD4）的通透性和 2-AG 水平。通过 Western blot 检测 MAGL 和紧密连接相关蛋白的表达。与对照组相比，WAS 大鼠的 MAGL 表达更高，2-AG 水平更低。给予 JZL184 后肠道通透性增加，这是由于紧密连接相关蛋白 Claudin-1、Claudin-2、Claudin-5 和 Occludin 的上调所致。MAGL 抑制的作用是通过 CB1 介导的，表明 MAGL 可能成为治疗慢性应激下肠道通透性降低的一个新靶点。
