Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
Laboratori de Química Farmacèutica (Unitat Associada al Consejo Superior de Investigaciones Científicas), Department de Farmacologia, Toxicologia i Química Farmacèutica, Facultat de Farmàcia i Ciències de de l'Alimentació y Institut de Biomedicina, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
Neurotherapeutics. 2020 Oct;17(4):1825-1835. doi: 10.1007/s13311-020-00854-1.
The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.
可溶性环氧化物水解酶（sEH）的抑制作用已在几种外周炎症相关疾病的临床治疗中显示出疗效，目前有 3 种化合物正在临床试验中。然而，该酶在神经炎症过程中的作用在很大程度上被忽视了。本文揭示了 sEH 作为治疗阿尔茨海默病（AD）的新靶标在药理学上的验证。我们使用 3 种结构不同且强效的 sEH 抑制剂作为化学探针，在 2 种与年龄相关的认知能力下降和 AD 模型中，评估认知障碍和病理特征。sEH 在 AD 患者的大脑中上调。我们的研究结果支持了中枢 sEH 抑制的有益作用，包括减轻认知障碍、神经炎症、tau 过度磷酸化病理和淀粉样斑块数量。这项研究表明，通过靶向 sEH 抑制大脑中的炎症是治疗 AD 的一种相关治疗策略。
