Soluble Epoxide Hydrolase As a Therapeutic Target for Neuropsychiatric Disorders

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 May 14

PMID 35563342

Authors

Jiajing Shan

Kenji Hashimoto

Affiliations

Soon will be listed here.

Abstract

It has been found that soluble epoxide hydrolase (sEH; encoded by the gene) in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation, which, in turn, plays a part in the pathogenesis of neuropsychiatric disorders. Meanwhile, epoxy fatty acids such as epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxyeicosapentaenoic acids (EDPs) have been found to exert neuroprotective effects in animal models of neuropsychiatric disorders through potent anti-inflammatory actions. Soluble expoxide hydrolase, an enzyme present in all living organisms, metabolizes epoxy fatty acids into the corresponding dihydroxy fatty acids, which are less active than the precursors. In this regard, preclinical findings using sEH inhibitors or knock-out (KO) mice have indicated that the inhibition or deficiency of sEH can have beneficial effects in several models of neuropsychiatric disorders. Thus, this review discusses the current findings of the role of sEH in neuropsychiatric disorders, including depression, autism spectrum disorder (ASD), schizophrenia, Parkinson's disease (PD), and stroke, as well as the potential mechanisms underlying the therapeutic effects of sEH inhibitors.

Citing Articles

The impact of the soluble epoxide hydrolase cascade on periodontal tissues.

Abdalla H, Van Dyke T Front Dent Med. 2025; 4:1129371.

PMID: 39916899 PMC: 11797759. DOI: 10.3389/fdmed.2023.1129371.

The Octadecanoids: Synthesis and Bioactivity of 18-Carbon Oxygenated Fatty Acids in Mammals, Bacteria, and Fungi.

Revol-Cavalier J, Quaranta A, Newman J, Brash A, Hamberg M, Wheelock C Chem Rev. 2024; 125(1):1-90.

PMID: 39680864 PMC: 11719350. DOI: 10.1021/acs.chemrev.3c00520.

Modeling enzyme competition in eicosanoid metabolism in macrophage cells using a cybernetic framework.

Khanum S, Gupta S, Maurya M, Raja R, Aboulmouna L, Subramaniam S J Lipid Res. 2024; 65(12):100666.

PMID: 39395792 PMC: 11728974. DOI: 10.1016/j.jlr.2024.100666.

Inhibition of Soluble Epoxide Hydrolase by Cembranoid Diterpenes from Soft Coral : Enzyme Kinetics, Molecular Docking, and Molecular Dynamics.

Phong N, Thao N, Vinh L, Luyen B, Minh C, Yang S Mar Drugs. 2024; 22(8).

PMID: 39195489 PMC: 11355918. DOI: 10.3390/md22080373.

Mice deficient in the phosphatase activity of sEH show decreased levels of the endocannabinoid 2-AG in the olfactory bulb and depressive-like behavior.

Oguro A, Kaga Y, Sato H, Fujiyama T, Fujimoto S, Nagai S FEBS Lett. 2024; 598(24):2980-2994.

PMID: 39034140 PMC: 11666072. DOI: 10.1002/1873-3468.14984.

References

Zhang L, Xu S, Wu X, Muse F, Chen J, Cao Y . Protective Effects of the Soluble Epoxide Hydrolase Inhibitor 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea in a Rat Model of Permanent Middle Cerebral Artery Occlusion. Front Pharmacol. 2020; 11:182. PMC: 7058996. DOI: 10.3389/fphar.2020.00182. View

Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa K . Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease. Proc Natl Acad Sci U S A. 2018; 115(25):E5815-E5823. PMC: 6016799. DOI: 10.1073/pnas.1802179115. View

Hashimoto K, Malchow B, Falkai P, Schmitt A . Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci. 2013; 263(5):367-77. DOI: 10.1007/s00406-013-0399-y. View

Giacobbe J, Benoiton B, Zunszain P, Pariante C, Borsini A . The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders. Front Psychiatry. 2020; 11:122. PMC: 7059745. DOI: 10.3389/fpsyt.2020.00122. View

Jackson-Lewis V, Przedborski S . Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc. 2007; 2(1):141-51. DOI: 10.1038/nprot.2006.342. View

Ma M, Ren Q, Fujita Y, Ishima T, Zhang J, Hashimoto K . Effects of AS2586114, a soluble epoxide hydrolase inhibitor, on hyperlocomotion and prepulse inhibition deficits in mice after administration of phencyclidine. Pharmacol Biochem Behav. 2013; 110:98-103. DOI: 10.1016/j.pbb.2013.06.005. View

Borsini A, Nicolaou A, Camacho-Munoz D, Kendall A, Di Benedetto M, Giacobbe J . Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis. Mol Psychiatry. 2021; 26(11):6773-6788. PMC: 8760043. DOI: 10.1038/s41380-021-01160-8. View

Capozzi M, Hammer S, McCollum G, Penn J . Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation. Sci Rep. 2016; 6:39211. PMC: 5155241. DOI: 10.1038/srep39211. View

Ren Q, Ma M, Ishima T, Morisseau C, Yang J, Wagner K . Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. Proc Natl Acad Sci U S A. 2016; 113(13):E1944-52. PMC: 4822604. DOI: 10.1073/pnas.1601532113. View

10.

Hirsch E, Hunot S . Neuroinflammation in Parkinson's disease: a target for neuroprotection?. Lancet Neurol. 2009; 8(4):382-97. DOI: 10.1016/S1474-4422(09)70062-6. View

11.

Borsini A . The role of soluble epoxide hydrolase and its inhibitors in depression. Brain Behav Immun Health. 2021; 16:100325. PMC: 7611634. DOI: 10.1016/j.bbih.2021.100325. View

12.

Hashimoto K, Hammock B . Reply to Reeves and Dunn: Risk for autism in offspring after maternal glyphosate exposure. Proc Natl Acad Sci U S A. 2021; 118(2). PMC: 7812790. DOI: 10.1073/pnas.2016496118. View

13.

Hashimoto K . Understanding the link between maternal infections and neurodevelopmental disorders in offspring: The role of abnormalities in metabolism of polyunsaturated fatty acids. Brain Behav Immun. 2019; 81:4-5. DOI: 10.1016/j.bbi.2019.07.010. View

14.

Zarriello S, Tuazon J, Corey S, Schimmel S, Rajani M, Gorsky A . Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders. Prog Neurobiol. 2018; 172:23-39. PMC: 6993804. DOI: 10.1016/j.pneurobio.2018.11.001. View

15.

Borsini A, Stangl D, Jeffries A, Pariante C, Thuret S . The role of omega-3 fatty acids in preventing glucocorticoid-induced reduction in human hippocampal neurogenesis and increase in apoptosis. Transl Psychiatry. 2020; 10(1):219. PMC: 7341841. DOI: 10.1038/s41398-020-00908-0. View

16.

Marsden C . Parkinson's disease. Lancet. 1990; 335(8695):948-52. DOI: 10.1016/0140-6736(90)91006-v. View

17.

Hao J, Chen Y, Yao E, Liu X . Soluble epoxide hydrolase inhibition alleviated cognitive impairments via NRG1/ErbB4 signaling after chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis in mice. Brain Res. 2018; 1699:89-99. DOI: 10.1016/j.brainres.2018.07.002. View

18.

Pu Y, Ma L, Shan J, Wan X, Hammock B, Hashimoto K . Autism-like Behaviors in Male Juvenile Offspring after Maternal Glyphosate Exposure. Clin Psychopharmacol Neurosci. 2021; 19(3):554-558. PMC: 8316667. DOI: 10.9758/cpn.2021.19.3.554. View

19.

LeWitt P, Chaudhuri K . Unmet needs in Parkinson disease: Motor and non-motor. Parkinsonism Relat Disord. 2020; 80 Suppl 1:S7-S12. DOI: 10.1016/j.parkreldis.2020.09.024. View

20.

Martini R, Siler D, Cetas J, Alkayed N, Allen E, Treggiari M . A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2021; 36(3):905-915. DOI: 10.1007/s12028-021-01398-8. View