Department of Anesthesiology, Taipei Veterans General Hospital; Department of Anesthesiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Chin J Physiol. 2022 Jan-Feb;65(1):1-11. doi: 10.4103/cjp.cjp_80_21.
Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid. The biological activity of EETs is terminated when being metabolized by soluble epoxide hydrolase (sEH), a process that serves as a key regulator of tissue EETs levels. EETs act through several signaling pathways to mediate various beneficial effects, including anti-inflammation, anti-apoptosis, and anti-oxidation with relieve of endoplasmic reticulum stress, thereby sEH has become a potential therapeutic target in cardiovascular disease and cancer therapy. Enzymes for EET biosynthesis and metabolism are both widely detected in both neuron and glial cells in the central nervous system (CNS). Recent studies discovered that astrocyte-derived EETs not only mediate neurovascular coupling and neuronal excitability by maintaining glutamate homeostasis but also glia-dependent neuroprotection. Genetic ablation as well as pharmacologic inhibition of sEH has greatly helped to elucidate the physiologic actions of EETs, and maintaining or elevating brain EETs level has been demonstrated beneficial effects in CNS disease models. Here, we review the literature regarding the studies on the bioactivity of EETs and their metabolic enzyme sEH with special attention paid to their action mechanisms in the CNS, including their modulation of neuronal activity, attenuation of neuroinflammation, regulation of cerebral blood flow, and improvement of neuronal and glial cells survival. We further reviewed the recent advance on the potential application of sEH inhibition for treating cerebrovascular disease, epilepsy, and pain disorder.
环氧二十碳三烯酸（EETs）是花生四烯酸经细胞色素 P450 加氧酶合成的脂肪酸信号分子。EETs 的生物活性在被可溶性环氧化物水解酶（sEH）代谢时终止，这一过程是组织 EETs 水平的关键调节剂。EETs 通过多种信号通路发挥作用，介导各种有益作用，包括抗炎、抗细胞凋亡和抗氧化，缓解内质网应激，因此 sEH 已成为心血管疾病和癌症治疗的潜在治疗靶点。EET 生物合成和代谢的酶在中枢神经系统（CNS）的神经元和神经胶质细胞中均广泛检测到。最近的研究发现，星形胶质细胞衍生的 EETs 通过维持谷氨酸稳态不仅介导神经血管偶联和神经元兴奋性，而且还具有依赖胶质的神经保护作用。sEH 的基因缺失和药理学抑制极大地帮助阐明了 EETs 的生理作用，并且在 CNS 疾病模型中已经证明了维持或提高脑 EETs 水平的有益效果。在这里，我们回顾了关于 EETs 的生物活性及其代谢酶 sEH 的研究文献，特别关注它们在中枢神经系统中的作用机制，包括它们对神经元活动的调节、神经炎症的减轻、脑血流的调节以及神经元和神经胶质细胞存活的改善。我们还进一步回顾了 sEH 抑制在治疗脑血管疾病、癫痫和疼痛障碍方面的潜在应用的最新进展。
