Review Article

Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors

Authors: Si-yu Ren1, Zhen-zhen Wang2, Yi Zhang3, Nai-hong Chen1,2
1 Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, China
2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3 Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
Correspondence to: Nai-hong Chen: chennh@imm.ac.cn,
DOI: 10.1038/s41401-020-0385-7
Received: 10 December 2019
Accepted: 19 February 2020
Advance online: 18 March 2020

Abstract

The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.
Keywords: Alzheimer's disease; Parkinson's disease; FAAH; MAGL; depression; anxiety

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