Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.
Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.
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DOI：
10.2174/1570159x13666150612225212
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发表时间：
2015
影响因子：
5.3
通讯作者：
Kunugi H
中科院分区：
文献类型：
--
作者：
Ogawa S;Kunugi H
大麻和Δ9-四氢大麻酚的类似物已用于治疗目的，但由于各种不良反应，其治疗用途仍然有限。内源性大麻素已经被发现，并且内源性大麻素信号传导的失调与重度抑郁症（MDD）的病理生理学有关。近年来，内源性大麻素水解酶如脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）已成为治疗MDD的新靶点。据报道，几种FAAH或MAGL抑制剂没有类似大麻的副作用，因此，对于一线抗抑郁药（选择性5-羟色胺和肾上腺素-去甲肾上腺素再摄取抑制剂）耐药的MDD患者来说，是新的潜在治疗选择。在这篇综述中，我们着重于MDD和内源性大麻素系统之间的可能关系以及抑制剂的治疗潜力。MAGL抑制剂可以通过激活大麻素受体2型来减少炎症反应。在下丘脑-垂体-肾上腺轴中，反复给予FAAH抑制剂可能有利于降低循环糖皮质激素水平。FAAH和MAGL抑制剂都可能有助于多巴胺能系统调节。近年来，几种新的抑制剂被开发出来，具有很强的效力和选择性。FAAH抑制剂、MAGL抑制剂或双重阻滞剂的使用将是有希望的MDD新治疗方法。使用这些抑制剂的进一步临床前研究和临床试验是必要的。
Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors’ therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic–pituitary–adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.