Blockade of Monoacylglycerol Lipase Inhibits Oligodendrocyte Excitotoxicity and Prevents Demyelination In Vivo
Blockade of Monoacylglycerol Lipase Inhibits Oligodendrocyte Excitotoxicity and Prevents Demyelination In Vivo
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DOI：
10.1002/glia.22742
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发表时间：
2015-01-01
期刊：
影响因子：
6.2
通讯作者：
Mato, Susana
中科院分区：
文献类型：
--
作者：
Bernal-Chico, Ana;Canedo, Manuel;Mato, Susana
内源性大麻素 2-araquidonoylglycerol (2-AG) 和 anandamide (AEA) 是生物活性脂质，在基础和病理条件下对脑功能的调节至关重要。阻断内源性大麻素代谢已成为治疗中枢神经系统炎症性疾病（包括多发性硬化症等髓鞘质疾病）的一种有前途的治疗策略。然而，内源性大麻素降解抑制剂在少突胶质细胞和白质束中的生物学作用仍然不明确。在这里，我们表明，选择性单酰基甘油脂肪酶 (MAGL) 抑制剂 JZL184 通过在体外少突胶质细胞中轻度激活 AMPA 受体来抑制细胞死亡，MAGL 底物 2-AG 和第二种主要内源性大麻素 AEA 以浓度依赖性方式模拟这种效应，而用 URB597 抑制 AEA 代谢酶脂肪酸酰胺水解酶则没有效果。药理学实验表明，少突胶质细胞免受 MAGL 阻断引起的兴奋性毒性的保护涉及大麻素 CB1 受体的激活和 AMPA 诱导的细胞溶质钙超载的减少、线粒体膜去极化和活性氧的产生。在治疗方案下施用 JZL184 可降低慢性实验性自身免疫性脑脊髓炎的临床严重程度、预防脱髓鞘并减少炎症。此外，在铜宗诱导的 T 细胞非依赖性脱髓鞘模型中，MAGL 失活有力地保留了髓磷脂的完整性并抑制了小胶质细胞的活化。这些发现表明 MAGL 阻断可能是治疗白质免疫依赖性和非免疫性损伤的有效策略。
The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.