title: Epoxyeicosatrienoic acids enhance axonal growth in primary sensory and cortical neuronal cell cultures.
abstract: It has recently been reported that soluble epoxide hydrolase (sEH), the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), is expressed in axons of cortical neurons; however, the functional relevance of axonal sEH localization is unknown. Immunocytochemical analyses demonstrate predominant axonal localization of sEH in primary cultures of not only cortical but also sympathetic and sensory neurons. Morphometric analyses of cultured sensory neurons indicate that exposure to a regioisomeric mixture of EETs (0.01-1.0 μM) causes a concentration-dependent increase in axon outgrowth. This axon promoting activity is not a generalized property of all regioisomers of EETs as axonal growth is enhanced in sensory neurons exposed to 14,15-EET but not 8,9- or 11,12-EET. 14,15-EET also promotes axon outgrowth in cultured cortical neurons. Co-exposure to EETs and either of two structurally diverse pharmacological inhibitors of sEH potentiates the axon-enhancing activity of EETs in sensory and cortical neurons. Mass spectrometry indicates that sEH inhibition significantly increases EETs and significantly decreases dihydroxyeicosatrienoic acid metabolites in neuronal cell cultures. These data indicate that EETs enhance axon outgrowth and suggest that axonal sEH activity regulates EETs-induced axon outgrowth. These findings suggest a novel therapeutic use of sEH inhibitors in promoting nerve regeneration.
authors.affiliation: Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Emun
authors.initials: E
authors.lastname: Abdu
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bruun
authors.forename: Dongren
authors.initials: D
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004537:Eicosanoic Acids / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects
chemical_list: D004537:Eicosanoic Acids; D004851:Epoxide Hydrolases