Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.
Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.
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DOI：
10.1016/j.pharmthera.2023.108394
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发表时间：
2023-04
影响因子：
13.5
通讯作者：
Chen, Chu
中科院分区：
文献类型：
--
作者：
Chen, Chu
关键词：
内源性大麻素是参与多种生理和病理过程的内源性脂质信号传导介质。2-花生四烯酰甘油（2-AG）是最丰富的内源性大麻素，是G蛋白偶联大麻素受体（CB 1 R和CB 2 R）的完全激动剂，这是大麻中主要精神活性成分Δ9-四氢大麻酚（Δ9-THC）的靶点。虽然2-AG已被公认为在脑中的抑制性GABA能和兴奋性谷氨酸能突触处调节突触传递和可塑性的逆行信使，但越来越多的证据表明2-AG还作为响应有害损伤的神经炎症的内源性终止剂起作用，从而维持脑内稳态。单酰基甘油脂肪酶（MAGL）是脑内降解2-AG的关键酶。2-AG的直接代谢产物是花生四烯酸（AA），它是一种白藜芦醇苷（PGs）和白三烯的前体。多项证据表明，MAGL的药理学或遗传失活可提高2-AG水平并减少其水解代谢产物，可解决神经炎症，减轻神经病理学，并改善神经退行性疾病动物模型中的突触和认知功能，包括阿尔茨海默病（AD）、多发性硬化症（MS）、帕金森病（PD）、和创伤性脑损伤（TBI）诱导的神经变性疾病。因此，已经提出MAGL是用于治疗神经退行性疾病的潜在治疗靶标。作为水解2-AG的主要酶，已经鉴定和开发了几种MAGL抑制剂。然而，我们对MAGL失活在神经退行性疾病中产生神经保护作用的机制的理解仍然有限。最近的一项研究发现，在星形胶质细胞中抑制2-AG代谢，而不是在神经元中，可以保护大脑免受TBI诱导的神经病理学的影响，这可能会为这个未解决的问题提供一些线索。本文综述了MAGL作为神经退行性疾病的潜在治疗靶点的研究进展，并讨论了抑制2-AG在脑内降解的神经保护作用的可能机制。
Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurodegenerative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in the brain.
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