Therapeutic potential of monoacylglycerol lipase inhibitors.
Therapeutic potential of monoacylglycerol lipase inhibitors.
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DOI：
10.1016/j.lfs.2012.10.025
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发表时间：
2013-03-19
期刊：
影响因子：
6.1
通讯作者：
Nomura, Daniel K.
中科院分区：
文献类型：
--
作者：
Mulvihill, Melinda M.;Nomura, Daniel K.
关键词：
大麻和阿司匹林几千年来一直被用来治疗包括疼痛和炎症在内的各种疾病。大麻等通过刺激大麻素受体发挥抗炎作用的大麻类化合物，以及阿司匹林等环氧合酶(COX)抑制剂，都在神经退行性疾病和癌症的小鼠模型中显示出有益的结果。然而，大麻素和COX抑制剂都有阻碍其长期使用的不良影响，分别包括认知障碍和胃肠道毒性。最近的研究发现，丝氨酸水解酶单酰甘油脂肪酶(MAGL)通过水解内源性大麻2-花生四烯基甘油(2-AG)将内源性大麻和二十烷基类化合物连接在一起，为特定组织中促炎症的花生四烯酸(AA)合成提供主要的花生四烯酸(AA)前体。近年来的研究表明，MAGL抑制剂通过增强内源性大麻素信号，在成瘾模式中诱导抗伤害性、缓解焦虑和止吐反应，并减轻沉淀性戒断症状。MAGL抑制剂还被证明在大脑中发挥抗炎作用，并通过降低二十烷类化合物的产生来保护神经退化。在癌症中，MAGL抑制剂不仅通过调节内源性大麻素-二十烷类化合物网络，而且通过控制脂肪酸的释放来合成促肿瘤信号脂类，被证明具有抗癌特性。因此，MAGL是在生理和疾病环境中同时协调多个脂质信号通路的关键节点。这篇综述将讨论MAGL的不同(病理)生理作用以及MAGL抑制剂在治疗一系列复杂的人类疾病中的治疗潜力。
Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown benefitial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid—eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.
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DOI：
10.18632/aging.100021
发表时间：
2009-02-11
期刊：
Aging
影响因子：
--
作者：
Choi SH;Bosetti F
通讯作者：
Bosetti F
影响因子：
3.6
作者：
Dinh, TP;Kathuria, S;Piomelli, D
通讯作者：
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影响因子：
8.6
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
Dinarello CA
影响因子：
3.6
作者：
Chanda, Pranab K.;Gao, Ying;Samad, Tarek A.
通讯作者：
Samad, Tarek A.