Rong Tang, Mengya Li, Banglian Hu, Guoqiang Fei, Honghua Zheng, Xin Wang, Jing Ding
EETs are endogenous multifaceted neuroprotective mediators that act through convergent anti-inflammatory, anti-apoptotic, and vascular mechanisms. sEH inhibition represents a highly attractive yet challenging therapeutic strategy for a wide spectrum of central nervous system disorders. Future progress requires: development of brain-penetrant or dual-target sEH inhibitors; identification of EET-specific G protein-coupled receptors (GPCRs) and biomarkers for patient stratification; improved preclinical models that better translate to humans; and rigorous clinical evaluation to define safety and efficacy.
BACKGROUND: Epoxyeicosatrienoic acids (EETs) are bioactive lipid mediators derived from arachidonic acid (ARA) via cytochrome P450 (CYP450) enzymes. They exert pleiotropic effects including anti-inflammation, anti-apoptosis, antioxidant activity, and vasodilation. Soluble epoxide hydrolase (sEH) rapidly hydrolyzes EETs to inactive diols, and its inhibition has emerged as a promising strategy to potentiate EET-mediated benefits. This review synthesizes current evidence on the roles and mechanisms of EETs and sEH in major neurological disorders and discusses translational challenges and future directions.
METHODS: A narrative review was conducted to synthesize evidence on the biosynthesis and metabolism of EETs, the expression and regulation of brain cytochrome P450 epoxygenases and sEH, the neuroprotective effects of EETs, and the therapeutic potential of sEH inhibitors, and to identify current limitations and future strategies for sEH-targeted therapies.
RESULTS: EETs ameliorate multiple neurological disorders through anti-inflammatory and anti-apoptotic effects, increased cerebral blood flow, reduced excitotoxicity, decreased dendritic spine loss, reduced oxidative stress, and enhanced neurosteroid secretion. In animal models, sEH inhibition elevates endogenous EET bioavailability, slows progression of various central nervous system diseases, and attenuates brain injury. However, sEH inhibitor development faces several challenges, including species differences in CYP expression, insufficient blood-brain barrier penetration, bleeding risks, failure of some candidates in late-stage trials, and the limitations of single-target inhibition.
CONCLUSIONS: EETs are endogenous multifaceted neuroprotective mediators that act through convergent anti-inflammatory, anti-apoptotic, and vascular mechanisms. sEH inhibition represents a highly attractive yet challenging therapeutic strategy for a wide spectrum of central nervous system disorders. Future progress requires: development of brain-penetrant or dual-target sEH inhibitors; identification of EET-specific G protein-coupled receptors (GPCRs) and biomarkers for patient stratification; improved preclinical models that better translate to humans; and rigorous clinical evaluation to define safety and efficacy.