Abstract
AbstractBackgroundEpoxy fatty acids (EpFAs) are cytochrome P450‐dependent derivatives of PUFAs with potent anti‐inflammatory, pro‐resolving properties. However, their activities are extremely short‐lived as soluble epoxide hydrolase (sEH) quickly converts EpFAs to pro‐inflammatory diols. Here we test the hypothesis that inhibition of sEH is a potential therapeutic approach for Alzheimer’s disease (AD) via increasing the anti‐inflammatory actions of EpFAs in the brain.MethodThe functional expression of sEH in the TgF344‐AD model of AD and the human AD brain tissue samples, compared with control brain samples, was studied using qPCR, immunohistochemistry, and Western blotting. An orally available specific sEH inhibitor called 1770 was investigated for its effects on rectifying AD‐like deficits by treating 12 months old TgF344‐AD mice with 3 mg/kg/day 1770 via drinking water for 4 months and evaluating them by neurobehavioral, electrophysiological, and neuropathological assessments.ResultsEH was found to be overexpressed in both TgF344‐AD rat and human AD brains. All assessments conducted in the open field maze showed no significant differences between groups. We observed sensorimotor gating deficits in TgF344‐AD rats using acoustic startle response and prepulse inhibition task, which were reversed by 1770 treatment. We further observed deficits in novel object recognition and step‐through passive avoidance tests in TgF344‐AD rats, which were also mitigated by 1770 treatment. Consistent with enhanced memory performance, 1770 treatment rectified hippocampal long‐term potentiation deficits seen in TgF344‐AD rats. Immunohistochemical stains showed that 1770 treatment reduced microglial activation and Aβ amyloid load. Transcriptomics profiling is being conducted to further analyze mechanisms induced by 1770.ConclusionBased on our rat model data and previous data using cell and mouse models, sEH inhibition is a promising therapeutic approach to AD. Investigating the pathways for EpFAs production, degradation, and signaling may provide exciting new mechanisms and therapeutic targets for chronic neuroinflammatory conditions such as AD.
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