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

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.