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2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics
Biological Psychiatry ( IF 10.6 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.biopsych.2020.01.015
Gaurav Bedse 1 , Mathew N Hill 2 , Sachin Patel 3
Affiliation  

Over the past decade there has been a surge of interest in the development of endocannabinoid-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty acid amide hydrolase to elevate levels of the endocannabinoid anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious endocannabinoid ligand, 2-arachidonoylglycerol (2-AG). We review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-related, and stress-related disorders; describe the current state of MAGL inhibitor drug development; and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.

中文翻译:

2-花生四烯酰甘油调节焦虑和压力适应:从草根到新疗法

在过去的十年中,人们对开发基于内源性大麻素的治疗方法来治疗各种神经精神疾病产生了浓厚的兴趣。虽然最初的临床前和临床开发工作侧重于对脂肪酸酰胺水解酶的药理学抑制以提高内源性大麻素 anandamide 的水平,但最近的努力集中在抑制单酰基甘油脂肪酶 (MAGL) 以增强最丰富和有效的内源性大麻素配体的信号传导,2 -花生四烯酰甘油(2-AG)。我们回顾了 2-AG 信号传导的生物化学和生理学,以及支持该系统在调节焦虑相关结果和压力适应中的作用的临床前证据。我们回顾了支持 MAGL 抑制治疗情感、创伤相关、和压力相关的疾病;描述 MAGL 抑制剂药物开发的现状;并讨论可能影响 MAGL 抑制剂功效的生物学因素。还讨论了与 MAGL 抑制剂临床进展相关的问题。我们谨慎乐观,因为 MAGL 抑制剂开发领域从临床前到临床和理论到实践,药理学 2-AG 增强可能代表一种治疗情感和压力相关神经精神疾病的机械新治疗方法。
更新日期:2020-10-01
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