IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.
Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
Mol Neurobiol. 2022 Jun;59(6):3485-3503. doi: 10.1007/s12035-022-02800-y. Epub 2022 Mar 26.
The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB and CB) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB and CB have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.
内源性大麻素系统（ECS）由内源性大麻素配体大麻素（AEA）和 2-花生四烯酰甘油（2-AG）、它们的靶标大麻素受体（CB 和 CB）以及参与其合成和代谢的酶（AEA 情况下的 N-酰基转移酶和脂肪酸酰胺水解酶（FAAH）和 2-AG 情况下的二酰基甘油脂肪酶（DAGL）和单酰基甘油脂肪酶（MAGL））组成。内源性大麻素系统在主要神经精神疾病中的功能障碍的起源仍有待确定，本文探讨了它们可能与慢性增加的硝基氧化应激和激活的免疫炎症途径相关的可能性，并研究了可能涉及的机制。炎症和硝基氧化应激与 CB 表达增加有关，这是通过 NADPH 氧化酶 NOX4 和 NOX1 的活性增加以及 CNR1 表达和 DNA 甲基化增加所致；通过促炎细胞因子水平增加、转录因子 Nrf2 结合到 CNR2 启动子区域的抗氧化反应元件以及 miR-139 的作用来增加 CB 上调。CB 和 CB 对氧化还原信号具有拮抗作用，这可能是由于 miRNA 实现的负反馈环所致。详细说明了炎症和氧化应激对内源性大麻素系统的影响，涉及 AEA 和 2-AG 水平，通过对钙稳态和磷脂酶 A 活性的影响；通过对 FAAH 活性的影响，通过功能性半胱氨酸和/或酪氨酸残基的硝化/亚硝化；以及通过对 2-AG 活性的影响，通过对 MGLL 表达和 MAGL 的影响。最后，基于这些详细的分子神经生物学机制，建议大麻二酚和富马酸二甲酯可能对重度抑郁症、双相情感障碍和精神分裂症具有治疗潜力。
