Role of Soluble Epoxide Hydrolase in Metabolism of PUFAs in Psychiatric and Neurological Disorders.

Kenji Hashimoto

doi:10.3389/fphar.2019.00036

Abstract

Inflammation plays a key role in the pathogenesis of a number of psychiatric and neurological disorders. Soluble epoxide hydrolases (sEH), enzymes present in all living organisms, metabolize epoxy fatty acids (EpFAs) to corresponding 1,2-diols by the addition of a molecule of water. Accumulating evidence suggests that sEH in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation. Preclinical studies demonstrated that protein expression of sEH in the prefrontal cortex, striatum, and hippocampus from mice with depression-like phenotype was higher than control mice. Furthermore, protein expression of sEH in the parietal cortex from patients with major depressive disorder was higher than controls. Interestingly, Ephx2 knock-out (KO) mice exhibit stress resilience after chronic social defeat stress. Furthermore, the sEH inhibitors have antidepressant effects in animal models of depression. In addition, pharmacological inhibition or gene KO of sEH protected against dopaminergic neurotoxicity in the striatum after repeated administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in an animal model of Parkinson’s disease (PD). Protein expression of sEH in the striatum from MPTP-treated mice was higher than control mice. A number of studies using postmortem brain samples showed that the deposition of protein aggregates of α-synuclein, termed Lewy bodies, is evident in multiple brain regions of patients from PD and dementia with Lewy bodies (DLB). Moreover, the expression of the sEH protein in the striatum from patients with DLB was significantly higher compared with controls. Interestingly, there was a positive correlation between sEH expression and the ratio of phosphorylated α-synuclein to α-synuclein in the striatum. In the review, the author discusses the role of sEH in the metabolism of PUFAs in inflammation-related psychiatric and neurological disorders.

Highlights

Polyunsaturated fatty acids (PUFAs) are generally considered to be necessary for maintaining normal physiology (Jump, 2002; Bazinet and Layé, 2014; Layé et al, 2018)
Total 14,15-EpETE [14,15epoxy-5Z,8Z,11Z,17Z-eicosatetraenoic acid], a soluble epoxide hydrolase (sEH) substrate, as well as sEH-derived free 14,15-DiHETrE [14,15-dihydroxy5Z,8Z,11Z- eicosatrienoic acid], decreased during winter compared to summer-fall, while sEH-derived total 7,8-DiHDPE [7,8-dihydroxy-4Z,10Z,13Z,16Z,19Z-docosapentaenoic acid], total 19,20-DiHDPE [19,20-dihydroxy-4Z,7Z,10Z,13Z,16Zdocosapentaenoic acid], and total 12,13-DiHOME [12,13-dihydroxy-9Z-octadecenoic acid] were increased during winter. These findings suggest that seasonal shifts in ω-6 and ω-3 PUFAs metabolism mediated by sEH may underlie inflammatory states in symptomatic depression with seasonal pattern (Hennebelle et al, 2017)
The prevention of relapse and recurrence is important in the management of depression

Summary

Introduction

Polyunsaturated fatty acids (PUFAs) are generally considered to be necessary for maintaining normal physiology (Jump, 2002; Bazinet and Layé, 2014; Layé et al, 2018). The author would like to discuss the role of soluble epoxide hydrolase (sEH) in the CYP-mediated metabolism of PUFAs which might be involved in the pathogenesis of psychiatric and neurological disorders. Ren et al (2016) reported that the sEH inhibitor TPPU [1-(1propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea] (Figure 2) conferred prophylactic and antidepressant effects in the LPS-induced inflammation model of depression while the current antidepressants showed no therapeutic effects in this model (Zhang et al, 2014).

Results

Conclusion