Fowler Christopher J
Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden.
Eur Neuropsychopharmacol. 2015 Jun;25(6):749-62. doi: 10.1016/j.euroneuro.2015.02.005. Epub 2015 Feb 28.
The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours.
内源性大麻素系统由大麻素CB1和CB2受体、它们的内源性配体花生四烯乙醇胺和2-花生四烯酸甘油、以及它们的合成和代谢酶组成，参与身体中的许多生物过程，从食欲到骨转换。抑制花生四烯乙醇胺和2-花生四烯酸甘油分解的化合物会提高这些脂质在大脑中的水平，从而调节内源性大麻素信号传导。在本综述中，从实际而非机制的角度讨论了这些酶是开发焦虑和抑郁新疗法的良好靶点的临床前证据。结论是，临床前数据很有前景，尽管不可逆的单酰基甘油脂肪酶抑制剂存在耐受性问题以及对学习和记忆的影响，并且仅以雄性啮齿动物为研究对象存在局限性。迄今为止，临床数据仅限于对花生四烯乙醇胺水解抑制剂的安全性研究，以及一项关于此类化合物在老年重度抑郁症患者中的尚未发表的研究，但在所使用的剂量方案下，它们耐受性良好，没有表现出“大麻样”行为的迹象。
