title: Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures.
abstract: In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.affiliation: Metabolomics Core Laboratory, Biomedical Research Center, Asan Institute of Life Sciences, Seoul, Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Wagner
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Hackett
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogawski
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D015777:Eicosanoids / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000378:metabolism*; D008297:Male; D051379:Mice; D012640:Seizures / Q000188:drug therapy* / Q000201:enzymology*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D015777:Eicosanoids; D005680:gamma-Aminobutyric Acid; D004851:Epoxide Hydrolases