Insights into the potential role of sEH inhibition in the prevention and progression of neurological disorders

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, which 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 executes a key factor in the metabolism of epoxy fatty acids, namely EETs, the byproducts of arachidonic acid mediated by the P450 pathway, which are transformed into their respective diols, known as dihydroxyeicosatrienoic acids (DHETs) from EET hydrolysis, which serve as sometimes 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. Further, EpFA, such as EETs, are best studied EpFA but are neither the most abundant nor the most potent. 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. • Soluble epoxide hydrolase (sEH) inhibitors may play a significant role in treating neurological diseases by enhancing the concentration of epoxy fatty acids (EpFAs), especially EETs. This causes dilation of blood vessels, inhibition of inflammation, neuronal protection, and prevention of oxidative stress. • sEH hydrolyzes EETs to less active, occasionally pro-inflammatory diols (DHETs); EETs are anti-inflammatory and neuroprotective. Inhibition of sEH maintains EETs. • Inhibition of sEH elevates EET levels. This can retard neurodegenerative disease progression by improving blood flow, inhibiting pro-inflammatory mediators, and protecting brain cells, emphasising a new therapeutic avenue for Alzheimer's disease.