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

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.

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Acknowledgments

This study was supported by the Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (Projects SAF2017-82771, SAF2016-77703, Fundació La Caixa (project CI18-00002) and SAF2015-68749) and Generalitat de Catalunya (2017 SGR 106). S.C. and E.P. thank the Universitat de Barcelona and the Institute of Biomedicine of the Universitat de Barcelona (IBUB), respectively, for PhD grants. R.L. and D.P.-I. thank the Ministerio de Educación, Cultura y Deporte for PhD grants (FPU program). We would also like to thank Xunta de Galicia (ED431C 2018/21) and Ministerio de Economía, Industria y Competitividad (Innopharma Project) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER). This study was also supported, in part, by grants from the National Institute of Environmental Health Sciences (NIEHS), the RIVER Award, NIEHS/R35 ES030443, and NIEHS Superfund Research Program P42 ES004699. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Highlights

• sEH levels are increased in the AD human brain and in murine models.

• Inhibition of sEH reduces oxidative stress and inflammation in murine AD models.

• AD hallmarks in AD mice models are reduced after treatment with sEH inhibitors.

• sEH inhibitors improve cognition in AD mice models.

• sEH can be proposed as a new pharmacological target for AD therapy.

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Griñán-Ferré, C., Codony, S., Pujol, E. et al. Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer’s Disease. Neurotherapeutics 17, 1825–1835 (2020). https://doi.org/10.1007/s13311-020-00854-1

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Key Words

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