Selective Inhibition of Alpha/Beta-Hydrolase Domain 6 Attenuates Neurodegeneration, Alleviates Blood Brain Barrier Breakdown, and Improves Functional Recovery in a Mouse Model of Traumatic Brain Injury
Selective Inhibition of Alpha/Beta-Hydrolase Domain 6 Attenuates Neurodegeneration, Alleviates Blood Brain Barrier Breakdown, and Improves Functional Recovery in a Mouse Model of Traumatic Brain Injury
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DOI：
10.1089/neu.2012.2647
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Zhang, Yumin
中科院分区：
文献类型：
--
作者：
Tchantchou, Flaubert;Zhang, Yumin
2-花生四烯甘油（2-AG）是中枢神经系统中最丰富的内源性大麻素，并且在脑损伤后升高。然而，由于其快速水解，2-AG的补偿和神经保护作用是短暂的。虽然抑制单酰基甘油脂酶（2-AG降解的主要酶）会导致大脑2-AG水平的大幅增加，但它也会导致大麻素受体脱敏和行为耐受。α/β水解酶结构域6（alpha/beta hydrolase domain 6，ABHD 6）是一种新型的2-AG水解酶，它对2-AG的水解起一小部分作用，但它的抑制作用被认为可以在治疗窗内提高2-AG的水平而不会引起副作用。使用创伤性脑损伤（TBI）的小鼠模型，我们发现用选择性ABHD 6抑制剂WWL 70进行的损伤后慢性治疗改善了运动协调和工作记忆表现。WWL 70治疗减少了皮质中的病变体积和齿状回中的神经变性。它还抑制了诱导型一氧化氮合酶和环氧合酶-2的表达，并在TBI后3天和7天增强了同侧皮质中的诱导型一氧化氮合酶-1的表达，表明小胶质细胞/巨噬细胞在治疗后从M1表型转变为M2表型。TBI后3天和7天的血脑屏障功能障碍显著减轻。此外，WWL 70的有益作用涉及大麻素1型和2型受体的上调和活化，并且归因于细胞外信号调节激酶和丝氨酸/苏氨酸蛋白激酶AKT的磷酸化。这项研究表明，通过调节ABHD 6活性来微调2-AG信号传导可以在TBI中发挥抗炎和神经保护作用。
2-arachidonylglycerol (2-AG) is the most abundant endocannabinoid in the central nervous system and is elevated after brain injury. Because of its rapid hydrolysis, however, the compensatory and neuroprotective effect of 2-AG is short-lived. Although inhibition of monoacylglycerol lipase, a principal enzyme for 2-AG degradation, causes a robust increase of brain levels of 2-AG, it also leads to cannabinoid receptor desensitization and behavioral tolerance. Alpha/beta hydrolase domain 6 (ABHD6) is a novel 2-AG hydrolytic enzyme that accounts for a small portion of 2-AG hydrolysis, but its inhibition is believed to elevate the levels of 2-AG within the therapeutic window without causing side effect. Using a mouse model of traumatic brain injury (TBI), we found that post-insult chronic treatment with a selective ABHD6 inhibitor WWL70 improved motor coordination and working memory performance. WWL70 treatment reduced lesion volume in the cortex and neurodegeneration in the dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3 and 7 days post-TBI, suggesting microglia/macrophages shifted from M1 to M2 phenotypes after treatment. The blood-brain barrier dysfunction at 3 and 7 days post-TBI was dramatically reduced. Furthermore, the beneficial effects of WWL70 involved up-regulation and activation of cannabinoid type 1 and type 2 receptors and were attributable to the phosphorylation of the extracellular signal regulated kinase and the serine/threonine protein kinase AKT. This study indicates that the fine-tuning of 2-AG signaling by modulating ABHD6 activity can exert anti-inflammatory and neuroprotective effects in TBI.