Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
PLoS One. 2022 Sep 9;17(9):e0268590. doi: 10.1371/journal.pone.0268590. eCollection 2022.
Chronic inflammation and blood-brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE2 and PGD2. In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood-brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro, with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood-brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood-brain barrier dysfunction caused by inflammatory insults.
慢性炎症和血脑屏障功能障碍是多发性硬化症、阿尔茨海默病和帕金森病等神经紊乱的关键病理特征。这些病理的主要驱动因素包括前列腺素等促炎刺激物，它们由环氧化酶 COX1 和 COX2 催化的花生四烯酸氧化在中枢神经系统中产生。单酰基甘油脂肪酶水解内源性大麻素信号脂质 2-花生四烯酸甘油，增强大脑中花生四烯酸的局部池，导致环氧化酶介导的前列腺素产生和神经炎症。最近的研究表明，单酰基甘油脂肪酶抑制剂是有效的抗炎调节剂，可增加 2-花生四烯酸甘油水平，同时降低花生四烯酸和前列腺素的水平，包括 PGE2 和 PGD2。在这项研究中，我们在脂多糖诱导的血脑屏障通透性的小鼠模型中以及神经血管单元的人和小鼠细胞（脑微血管内皮细胞、周细胞和星形胶质细胞）中表征了一种新型、高选择性、有效和可逆的单酰基甘油脂肪酶抑制剂（MAGLi 432）。我们在体外证实了单酰基甘油脂肪酶在特定的神经血管单元细胞中的表达，其中周细胞的表达水平和活性最高。然而，MAGLi 432 并没有改善体内脂多糖诱导的血脑屏障通透性，也没有减少大脑中促炎细胞因子的产生。我们的数据证实了单酰基甘油脂肪酶在小鼠和人神经血管单元细胞中的表达，并为进一步在炎症损伤引起的血脑屏障功能障碍背景下对 MAGLi 432 进行特定细胞分析提供了基础。
