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Publication Detail

Title: Inhibition of sEH via stabilizing the level of EETs alleviated Alzheimer's disease through GSK3β signaling pathway.

Authors: Sun, Cheng-Peng; Zhang, Xin-Yue; Zhou, Jun-Jun; Huo, Xiao-Kui; Yu, Zhen-Long; Morisseau, Christophe; Hammock, Bruce D; Ma, Xiao-Chi

Published In Food Chem Toxicol, (2021 Oct)

Abstract: 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.

PubMed ID: 34411643 Exiting the NIEHS site

MeSH Terms: Alzheimer Disease/chemically induced*; Amyloid beta-Peptides/toxicity*; Animals; Eicosanoids/metabolism*; Epoxide Hydrolases/genetics; Epoxide Hydrolases/metabolism*; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta/genetics; Glycogen Synthase Kinase 3 beta/metabolism*; Memory Disorders; Mice; Mice, Inbred C57BL; Phenylurea Compounds/pharmacology*; Piperidines/pharmacology*; Signal Transduction; Spatial Learning/drug effects

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