Health Science Center, Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas, San Antonio, TX 78229, USA.
Cells. 2021 Nov 2;10(11):2979. doi: 10.3390/cells10112979.
Traumatic brain injury (TBI) represents a major cause of morbidity and disability and is a risk factor for developing neurodegenerative diseases, including Alzheimer's disease (AD). However, no effective therapies are currently available for TBI-induced AD-like disease. Endocannabinoids are endogenous lipid mediators involved in a variety of physiological and pathological processes. The compound 2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid with profound anti-inflammatory and neuroprotective properties. This molecule is predominantly metabolized by monoacylglycerol lipase (MAGL), a key enzyme degrading about 85% of 2-AG in the brain. Studies using animal models of inflammation, AD, and TBI provide evidence that inactivation of MAGL, which augments 2-AG signaling and reduces its metabolites, exerts neuroprotective effects, suggesting that MAGL is a promising therapeutic target for neurodegenerative diseases. In this short review, we provide an overview of the inhibition of 2-AG metabolism for the alleviation of neuropathology and the improvement of synaptic and cognitive functions after TBI.
创伤性脑损伤 (TBI) 是发病率和致残率的主要原因，也是包括阿尔茨海默病 (AD) 在内的神经退行性疾病的危险因素。然而，目前尚无有效的疗法可用于治疗 TBI 诱导的 AD 样疾病。内源性大麻素是参与多种生理和病理过程的内源性脂质介质。化合物 2-花生四烯酸甘油酯 (2-AG) 是含量最丰富的内源性大麻素，具有很强的抗炎和神经保护特性。这种分子主要由单酰基甘油脂肪酶 (MAGL) 代谢，该酶可降解大脑中约 85%的 2-AG。使用炎症、AD 和 TBI 的动物模型进行的研究提供了证据，表明 MAGL 的失活会增强 2-AG 信号并减少其代谢物，从而发挥神经保护作用，这表明 MAGL 是神经退行性疾病的一个有希望的治疗靶点。在这篇简短的综述中，我们概述了抑制 2-AG 代谢以减轻 TBI 后的神经病理学、改善突触和认知功能。
