Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.
Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.
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DOI：
10.1161/strokeaha.117.019664
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发表时间：
2018-03
期刊：
影响因子：
8.3
通讯作者：
Silva AC
中科院分区：
文献类型：
--
作者：
Choi SH;Arai AL;Mou Y;Kang B;Yen CC;Hallenbeck J;Silva AC
单酰基甘油脂肪酶(MAGL)是一种酶，它能水解内源性大麻素-2-花生四烯基甘油，并调节花生四烯酸和前列腺素的产生，这两种物质是组织炎症反应的中介物质。在此，我们研究了选择性MAGL抑制剂JZL184和MJN110对3种不同的局灶性脑缺血模型的作用及其分子机制。自发性高血压大鼠和血压正常的Wistar-京都大鼠采用皮质内注射强效血管收缩因子-1、开颅手术永久性阻断大脑中动脉(MCA)远端段或腔内线栓法短暂阻断MCA的方法。局灶性脑缺血60min后分别给予JZL184或MJN110。通过磁共振成像、组织学和行为学测试，在第1天到第28天期间评估梗塞体积、大脑半球肿胀和功能结果。MAGL的药理抑制作用可显著减轻脑梗塞体积和大脑半球肿胀。MAGL抑制还可改善感觉运动障碍，抑制炎症反应，减少变性神经元的数量。MAGL抑制的这些有益作用不能被大麻受体的选择性拮抗剂完全消除，这表明抗炎作用是通过抑制二十烷基类化合物的产生而不是通过激活大麻素受体来实现的。提示MAGL可能参与了局灶性脑缺血的病理生理过程，有望成为治疗缺血性卒中的靶点。
Monoacylglycerol lipase (MAGL) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates production of arachidonic acid and prostaglandins, substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. Spontaneously hypertensive rats and normotensive Wistar-Kyoto rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery (MCA) via craniectomy, or transient occlusion of the MCA by the intraluminal suture method. JZL184 or MJN110 were administered 60 min after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between day 1 to day 28 by magnetic resonance imaging, histology, and behavioral tests. Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors. Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.