Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer’s Disease

Christian Griñán-Ferré*, Sandra Codony, Eugènia Pujol, Jun Yang, Rosana Leiva, Carmen Escolano, Dolors Puigoriol-Illamola, Júlia Companys-Alemany, Rubén Corpas, Coral Sanfeliu, Belen Pérez, M. Isabel Loza, José Brea, Christophe Morisseau, Bruce D. Hammock, Santiago Vázquez, Mercè Pallàs, Carles Galdeano

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1825-1835
Number of pages11
JournalNeurotherapeutics
Volume17
Issue number4
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Druggability
  • Inflammation
  • Soluble epoxide hydrolase
  • Target engagement
  • Tau
  • β-amyloid

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