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


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    D. Krstic, I. Knuesel, Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25–34 (2012).

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    V. Calsolaro, P. Edison, Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimer’s Dementia 12, 719–732 (2016).

    PubMed  Article  Google Scholar 

  3. 3.

    W.-Y. Fu, X. Wang, N. Y. Ip, Targeting neuroinflammation as a therapeutic strategy for Alzheimer’s disease: mechanisms, drug candidates, and new opportunities. ACS Chem. Neurosci. 10, 872-879 (2019).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    A. T. Kodamullil, F. Zekri, M. Sood et al. Tracing investment in drug development for Alzheimer disease. Nat. Rev. Drug Discovery 16, 819 (2017).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    E. Tönnies, E. Trushina, Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J. Alzheimer’s Dis. 57, 1105–1121 (2017).

    Article  CAS  Google Scholar 

  6. 6.

    K. J. Barnham, C. L. Masters, A. I. Bush, Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discovery 3, 205-214 (2004).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    M. T. Heneka, M. J. Carson, J. El Khoury et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    F. L. Heppner, R. M. Ransohoff, B. Becher, Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    S. Makin, The amyloid hypothesis on trial. Nature 559, S4-S7 (2018).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    B. Inceoglu, A. Bettaieb, F. G. Haj, A. V. Gomes, B. D. Hammock, Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors. Prostaglandins Other Lipid Mediators 133, 68–78 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    X. Liu, C. M. Davis, N. J. Alkayed, P450 eicosanoids and reactive oxygen species interplay in brain injury and neuroprotection. Antioxid. Redox Signaling 28, 987–1007 (2018).

    CAS  Article  Google Scholar 

  12. 12.

    A. Marowsky, J. Burgener, J. R. Falck, J. M. Fritschy, M. Arand, Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism. Neuroscience 163, 646–661 (2009).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    P. Sura, R. Sura, A. E. EnayetAllah, D. F. Grant, Distribution and expression of soluble epoxide hydrolase in human brain. J. Histochem. Cytochem. 56, 551–559 (2007).

    Article  CAS  Google Scholar 

  14. 14.

    C. Morisseau, B. D. Hammock, Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu. Rev. Pharmacol. Toxicol. 53, 37–58 (2013).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    L. Wang, G. Luo, L. F. Zhang, H. X. Geng, Neuroprotective effects of epoxyeicosatrienoic acids. Prostaglandins Other Lipid Mediators 138, 9–14 (2018).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    K. M. Wagner, C. B. McReynolds, W. K. Schmidt, B. D. Hammock, Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol. Ther. 180, 62–76 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    H.T. Lee, K.I. Lee, C.H. Chen, T.S. Lee. Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer’s disease. J. Neuroinflammation 16, 267 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    J. E. Morley, S. A. Farr, J. F. Flood, Antibody to amyloid β protein alleviates impaired acquisition, retention, and memory processing in SAMP8 mice. Neurobiol. Learn. Mem. 78, 125–138 (2002).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    T. Takeda, Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem. Res. 34, 639–659 (2009).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    I. Akiguchi, M. Pallàs, H. Budka et al. SAMP8 mice as a neuropathological model of accelerated aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology 37, 293–05 (2017).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    M. Pallàs, Senescence-accelerated mice P8: a tool to study brain aging and Alzheimer’s disease in a mouse model. ISRN Cell Biol. 2012, 917167 (2012).

    Article  Google Scholar 

  22. 22.

    C. Griñan-Ferré, V. Palomera-Ávalos, D. Puigoriol-Illamola et al. Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence. Exp. Gerontol. 80, 57–69 (2016).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    H. Oakley, S. L. Cole, S. Logan et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    R. Kimura, M. Ohno, Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5xFAD Alzheimer mouse model. Neurobiol Dis. 33, 229–235 (2009).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    C. H. Arrowsmith, J. E. Audia, C. Austin, et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536–541 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    T. E. Rose, C. Morisseau, J. Y. Liu et al. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics and reduction of inflammatory pain. J. Med. Chem. 53, 7067–7075 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    M. Miura, I. Sato, H. Kiyohara, et al. Cyclic amino compound, or salt thereof. JP2011016743 (2011).

  28. 28.

    S. Vázquez, E. Valverde, R. Leiva, M. Vázquez-Carrera, S. Codony, Analogs of adamantylureas as soluble epoxide hydrolase inhibitors. WO 2017017048 (2017).

  29. 29.

    A. I. Ostermann, J. Herbers, I. Willenberg et al. Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl-)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): resulting drug levels and modulation of oxylipin pattern. Prostaglandins Other Lipid Mediators 121, 131–137 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    N. Taguchi, S. Nakayama, M. Tanaka. Single administration of soluble epoxide hydrolase inhibitor suppresses neuroinflammation and improves neuronal damage after cardiac arrest in mice. Neurosci. Res. 111, 56–63 (2016).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    M. Ma, Q. Ren, Y. Fujita, T. Ishima, J. C. Zhang, K. Hashimoto, Effects of AS2586114, a soluble epoxide hydrolase inhibitor, on hyperlocomotion and prepulse inhibition deficits in mice after administration of phencyclidine. Pharmacol. Biochem. Behav. 110, 98–103 (2013).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    S. H. Hwang, H. J. Tsai, J. Y. Liu, C. Morisseau, B. D. Hammock, Orally bioavailable potent soluble epoxide hydrolase inhibitors. J. Med. Chem. 50, 3825-3840 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    R. Chen, E. Whitcomb, V. MacIntyre, et al. Pharmacokinetics and pharmacodynamics of AR9281, an inhibitor of soluble epoxide hydrolase, in single- and multiple-dose studies in healthy human subjects. J. Clin. Pharmacol. 52, 319–328 (2013).

    Article  CAS  Google Scholar 

  34. 34.

    L. Di, E.H. Kerns, K. Fan, O. J. McConnell, G.T. Carter. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem. 38, 223-232 (2003).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    R. Martínez Molina, M. Jafari, M. Ignatushchenko, et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    S.S. Shaftel, S. Kyrkanides, J.A. Olschowka, J.H. Miller, R.E. Johnson, M.K. O’Banion. Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 117(6), 1595–1604 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    H. Schneider, F. Pitossi, D. Balschun, A. Wagner, A. del Rey, H.O.Besedovsky HO. A neuromodulatory role of interleukin-1beta in the hippocampus. Proc. Natl. Acad. Sci. U. S. A. 95, 7778-83 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    A.V. Andjelkovic, D. Kerkovich, J. Shanley, L. Pulliam, J.S. Pachter. Expression of binding sites for beta chemokines on human astrocytes. Glia. 28, 225-35 (1999).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    M. T. Heneka, R. M. McManus, E. Latz, Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 19, 610–621 (2018).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Z. Si, X. Wang, Z. Zhang et al. Heme oxygenase 1 induces tau oligomer formation and synapse aberrations in hippocampal neurons. J. Alzheimers Dis. 65, 409–419 (2018).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    R. M. Wright, L. K. Weigel, M. Varella-Garcia, G. Vaitaitis, J. E. Repine, Molecular cloning, refined chromosomal mapping and structural analysis of the human gene encoding aldehyde oxidase (AOX1), a candidate for the ALS2 gene. Redox Rep. 3, 135–144 (2016).

    Article  Google Scholar 

  42. 42.

    K. Murakami, N. Murata, Y. Noda, et al. SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease. J. Biol. Chem. 286, 44557–44568 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    C. Hetz, S. Saxena, ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 13, 477–491 (2017).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    C. Corona, A. Pensalfini, V. Frazzini, S. L. Sensi, New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis. 2, e176 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    H. Zempel, E. Thies, E. Mandelkow, E. M. Mandelkow, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    S. D. Girard, K. Baranger, C. Gauthier, M. Jacquet et al. Evidence for early cognitive impairment related to frontal cortex in the 5XFAD mouse model of Alzheimer's disease. J. Alzheimers Dis. 33, 781–796 (2013).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    J .Couturier, I.C. Stancu, O. Schakman et al. Activation of phagocytic activity in astrocytes by reduced expression of the inflammasome component ASC and its implication in a mouse model of Alzheimer disease. J Neuroinflammation. 27, 13-20 (2016).

  48. 48.

    A. L. Lazaar, L. Yang, R. L. Boardley, N. S. Goyal et al. Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor. Br. J. Clin. Pharmacol. 81, 971–979 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    H. Braak, E. Braak, in Cerebral Cortex, Neurodegenerative and age-related changes in structure and function of cerebral cortex, A. Peters, J. H. Morrison, Eds. (Kluwer Academic/Plenum Publisher, New York, 1999), vol. 14, pp. 475–512.

  50. 50.

    J Bhattacharya S, Maelicke A, Montag D. Nasal application of the galantamine pro-drug Memogain slows down plaque deposition and ameliorates behavior in 5X Familial Alzheimer’s disease mice. Alzheimers Dis. 46,123-36(2015)

Download references


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.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information



Corresponding authors

Correspondence to Christian Griñán-Ferré or Santiago Vázquez or Mercè Pallàs or Carles Galdeano.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


• 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.

Electronic supplementary material


(PDF 1.12 kb)


(PDF 515 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Key Words

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