Effects of a diet high in omega-3 polyunsaturated fatty acids (PUFAs) on inhibition of soluble epoxide hydrolase (sEH) and mitigation of painful docetaxel-induced peripheral neuropathy in mice.

Abstract

140 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and frequently persistent and debilitating toxicity of cancer treatment that greatly affects the quality of life of cancer survivors. There is an unmet need for effective treatments against established CIPN and for preventative approaches. The enzyme soluble epoxide hydrolase (sEH) converts epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding pro-inflammatory and hyperalgesic dihydroxy metabolites (diols). Thus, sEH is a master regulator of inflammation. The sEH inhibitor (sEHI) EC5026 has completed phase 1 studies in healthy volunteers, with no significant adverse effects noted. The EpFAs of the ω-3 PUFAs are particularly effective at promoting analgesia and resolution of inflammation, suggesting that a diet rich in ω-3 PUFAs would enhance the inflammation-resolving effects of a sEHI. Methods: We examined the prophylactic efficacy of the sEHI EC5026 in a mouse model of docetaxel-induced painful neuropathy, by measuring mechanical hind paw withdrawal thresholds (PWTs) using an electronic von Frey aesthesiometer (IITC, Woodland Hills, CA). EC5026 was formulated in the drinking water at a concentration calculated to provide the mice with a dose of ~5 mg/kg/day through their daily unrestricted water intake. In addition, we studied docetaxel-induced CIPN in adult sEH ( Ephx2 ) male homozygous knock-out (KO) mice and wild-type (WT) mice on a diet high in ω-3 PUFAs vs a diet high in ω-6 PUFAs (both from Research Diets Inc., New Brunswick, NJ), starting 3 weeks prior to beginning docetaxel treatment and continued throughout the duration of the experiment. We also measured the levels of non-esterified PUFAs and their corresponding EpFAs and diols by UPLC-MS/MS in mouse plasma. Results: Docetaxel decreased the PWT in male C57BL/6J WT mice, while prophylactic administration of EC5026 mitigated this neuropathic allodynia. After 3 weeks on the ω-3 vs ω-6 diet, the respective PUFAs and their corresponding dihydroxy metabolites were significantly enriched. As expected, genetic ablation of Ephx2 increased the plasma levels of the corresponding epoxides. Importantly, sEH KO mice exhibited less severe docetaxel-induced CIPN and recovered from it faster than their WT counterparts when fed a diet high in ω-3 PUFAs, but not when fed a diet high in ω-6 PUFAs. Conclusions: We propose that sEH is a druggable therapeutic target in CIPN pathophysiology. The benefits of targeting sEH can be augmented by a diet rich in omega-3 PUFAs.