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

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.

Keywords: Druggability; Inflammation; Soluble epoxide hydrolase; Target engagement; Tau; β-amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology
  • Animals
  • Benzoates / pharmacology
  • Benzoates / therapeutic use*
  • Bridged Bicyclo Compounds / pharmacology
  • Bridged Bicyclo Compounds / therapeutic use*
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / biosynthesis*
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Humans
  • Mice
  • Mice, Transgenic


  • 3-cyclopropyl-4-(4-(2-(((6,6-dimethylbicyclo(3.1.1)heptan-2-yl)methyl)amino)-2-oxoethyl)piperidin-1-yl)benzoic acid
  • Benzoates
  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • Epoxide Hydrolases
  • EPHX2 protein, human