Université Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, CHAM7230, Av. E. Mounier 72, 1200 Bruxelles, Belgium.
FASEB J. 2011 Aug;25(8):2711-21. doi: 10.1096/fj.10-176602. Epub 2011 May 6.
Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2-arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here.
炎症性肠病（IBD）是一种慢性炎症性疾病，需要新的治疗方法。遗传和药理学数据表明，CB（1）和 CB（2）大麻素受体的激活在 IBD 实验模型中具有保护作用。因此，增加这些受体的主要全激动剂 2-花生四烯酸甘油的内源性水平应该对结肠炎有有益的影响。通过抑制单酰基甘油脂肪酶（MAGL），即负责水解 2-花生四烯酸甘油的主要酶，用选择性抑制剂 JZL184 在三硝基苯磺酸（TNBS）诱导的结肠炎小鼠模型中提高 2-花生四烯酸甘油的水平，在患病小鼠中抑制 MAGL 增加了 2-花生四烯酸甘油的水平，导致宏观和组织学结肠改变以及结肠促炎细胞因子表达减少。MAGL 抑制后肠屏障功能的完整性恢复导致内毒素血症减少以及外周和大脑炎症减少。与 JZL184 联合使用 CB（1）（SR141716A）或 CB（2）（AM630）选择性拮抗剂完全消除了 MAGL 抑制对 TNBS 诱导的结肠改变的保护作用，从而证明了两种大麻素受体的参与。总之，增加 2-花生四烯酸甘油的水平导致结肠炎以及相关的全身和中枢炎症显著减少。这可能为基于此处描述的 2-花生四烯酸甘油的新保护作用的 IBD 治疗提供新的药理学方法。
