Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Abstract

Eicosanoids are biologically active lipid signaling molecules derived from polyunsaturated fatty acids. Many of the actions of eicosanoid metabolites formed by cyclooxygenase and lipoxygenase enzymes have been characterized, however, the epoxy-fatty acids (EpFAs) formed by cytochrome P450 enzymes are newly described by comparison. The EpFA metabolites modulate a diverse set of physiologic functions that include inflammation and nociception among others. Regulation of EpFAs occurs primarily via release, biosynthesis and enzymatic transformation by the soluble epoxide hydrolase (sEH). Targeting sEH with small molecule inhibitors has enabled observation of the biological activity of the EpFAs in vivo in animal models, greatly contributing to the overall understanding of their role in the inflammatory response. Their role in modulating inflammation has been demonstrated in disease models including cardiovascular pathology and inflammatory pain, but extends to neuroinflammation and neuroinflammatory disease. Moreover, while the EpFA demonstrate activity against inflammatory pain, interestingly, this action extends to blocking chronic neuropathic pain as well. This review outlines the role of modulating sEH and the biological action of EpFA in models of pain and inflammatory diseases.

Inactivation of Cys674 in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase

“…Podocyte‐specific sEH deficiency reduces ER stress and renal fibrosis under hyperglycaemia (Bettaieb et al, ). Inhibition of sEH stabilizes epoxy fatty acids to reverse ER stress (Wagner et al, ). Similar to these findings, we confirm that sEH can positively regulate ER stress in the renal cortex.…”

“…Podocyte-specific sEH deficiency reduces ER stress and renal fibrosis under hyperglycaemia (Bettaieb et al, 2017). Inhibition of sEH stabilizes epoxy fatty acids to reverse ER stress (Wagner et al, 2017).…”

“…Several studies indicate that sEH could regulate ER stress (Bettaieb et al, 2017;Harris et al, 2015;Wagner, McReynolds, Schmidt, & Hammock, 2017), so we applied the sEH inhibitor TPPU to RPT cells from both WT mice and SKI mice. In WT RPT cells, TPPU itself did not affect the expression of sEH compared with solvent control, nor did it affect the expression of ER stress markers and D 1 receptors F I G U R E 5 Inhibition of ER stress reverses the expression of sEH and D 1 receptors in primary SKI RPT cells.…”

Chiral lipidomics of monoepoxy and monohydroxy metabolites derived from long-chain polyunsaturated fatty acids

“…Moreover, we observed that the fold-change was much more pronounced with the enantiomers than with the total levels of the corresponding regioisomers. This shift in enantiomeric composition has not been analyzed before, but might have significantly contributed to the beneficial effects of genetic or pharmacological sEH inhibition as observed in various animal models of cardiovascular and inflammatory diseases (24,25,39,40). Also, the enantioselectivity of mEH may provide a novel clue for understanding the role of this enzyme in human diseases (41,42).…”

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

“…This suggests that increased expression of antioxidant enzymes and reduction in ROS production mediated by EETs [137, 140] may lead to decreased ER stress. Thus, additional studies are needed to decipher the precise molecular mechanisms underlying regulation of ER stress by sEH and the contribution of ER stress to the beneficial effects of sEH deficiency and inhibition [141]. …”