Endocrine and Metabolic Science · Published 2025-10-07 · DOI 10.1016/j.endmts.2025.100277
Neurological disorders are associated with decreased blood supply to the brain, neuronal damage, oxidative stress, and inflammation. While treatments are limited, soluble epoxide hydrolase inhibitors can be useful in alleviating neurological disorders via increasing or maintaining the levels of epoxy fatty acids (EpFAs), which modulate multiple biological pathways to dilate blood vessels, protect neurones, alleviate inflammation, and reduce oxidative stress. Enzyme soluble epoxide hydrolase (sEH), with dual function, is found in multiple tissues, including the brain. It is extensively expressed in neurones, astrocytes, and CNS vasculature in the cortex and hippocampus, suggesting its significant role in neurological functions. It is a key factor in the metabolism of EpFAs, namely epoxyeicodatrienoic acids (EETs), the byproducts of arachidonic acid mediated by the P450 pathway, which are transformed into their respective diols, known as dihydroxyeicosatrienoic acids (DHETs), which are proinflammatory agents and are less potent compared to EETs. EETs suppress the generation of pro-inflammatory signalling molecules and other inflammatory mediators, aiding in the resolution of inflammation. Inhibiting sEH elevates the concentration of EETs and other structurally similar EpFAs while reducing the release of nitric oxide metabolites and pro-inflammatory cytokines. EETs act as potential endothelial-derived hyperpolarizing factors (EDHFs), which promote vascular health through the hyperpolarization and relaxing of the vascular smooth muscle cells. The vasodilatory effect of EETs improves blood flow to the brain and other tissues, which support neuronal health and function. The elevated levels of EETs provide cytoprotection to brain cells, potentially slowing the progression of neurodegeneration. Modulating EETs by inhibiting sEH presents an emerging therapy for addressing neurological diseases. Ultimately, this review explores the influence of soluble epoxide hydrolase inhibitors in preventing the progression of neurodegenerative diseases.
Abstract from DOAJ. Public domain (CC0 1.0).
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