title: Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice.
abstract: The soluble epoxide hydrolase (sEH) is a regulatory enzyme responsible for the metabolism of bioactive lipid epoxides of both omega-6 and omega-3 long chain polyunsaturated fatty acids. These natural epoxides mediate cell signaling in several physiological functions including blocking inflammation, high blood pressure and both inflammatory and neuropathic pain. Inhibition of the sEH maintains the level of endogenous bioactive epoxy-fatty acids (EpFA) and allows them to exert their generally beneficial effects. The Akita (Ins2Akitaor Ins2C96Y) mice represent a maturity-onset of diabetes of the young (MODY) model in lean, functionally unimpaired animals, with a sexually dimorphic disease phenotype. This allowed for a test of male and female mice in a battery of functional and nociceptive assays to probe the role of sEH in this system. The results demonstrate that inhibiting the sEH is analgesic in diabetic neuropathy and this occurs in a sexually dimorphic manner. Interestingly, sEH activity is also sexually dimorphic in the Akita model, and moreover correlates with disease status particularly in the hearts of male mice. In addition, in vivo levels of oxidized lipid metabolites also correlate with increased sEH expression and the pathogenesis of disease in this model. Thus, sEH is a target to effectively block diabetic neuropathic pain but also demonstrates a potential role in mitigating the progression of this disease.
authors.affiliation: Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California Davis, Davis, CA 95616, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gilda
authors.affiliation: Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States.
authors.forename: Debin
authors.initials: D
authors.lastname: Wan
authors.affiliation: Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California Davis, Davis, CA 95616, United States.
authors.forename: Aldrin V
authors.initials: AV
authors.lastname: Gomes
authors.affiliation: Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy / Q000201:enzymology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012727:Sex Characteristics
chemical_list: C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D005227:Fatty Acids; D010671:Phenylurea Compounds; D004851:Epoxide Hydrolases
keywords: Anti-nociception; Chronic pain; Diabetic neuropathy; Epoxy-fatty acid (EpFA); Soluble epoxide hydrolase (sEH)