The Second Affiliated Hospital, College of Pharmacy, Institute of Integrative Medicine, Dalian Medical University, Dalian, China.
Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, United States.
Food Chem Toxicol. 2021 Oct;156:112516. doi: 10.1016/j.fct.2021.112516. Epub 2021 Aug 16.
Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是痴呆。可溶性环氧化物水解酶（sEH）的抑制作用可调节涉及中枢神经系统（CNS）疾病的炎症。然而，sEH 在 AD 中的确切机制尚不清楚。在这项研究中，我们评估了 sEH 在淀粉样β（Aβ）诱导的 AD 小鼠中的重要作用，并揭示了抑制 sEH 治疗 AD 的可能分子机制。结果表明，sEH 的表达和活性在 Aβ 诱导的 AD 小鼠海马体中显著增加。通过 TPPU（一种选择性 sEH 抑制剂）抑制 sEH，可缓解 Aβ 诱导的 AD 小鼠的空间学习和记忆缺陷，并提高神经递质水平。此外，抑制 sEH 通过稳定体内环氧二十碳三烯酸（EETs）的水平（特别是 8,9-EET 和 14,15-EET），可改善神经炎症、神经元死亡和氧化应激，进而通过调节 GSK3β 介导的 NF-κB、p53 和 Nrf2 信号通路发挥抗 AD 作用。这些发现揭示了 sEH 作为治疗 AD 的潜在治疗靶点的潜在机制。
