title: Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress.
abstract: Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Tamaki
authors.initials: T
authors.lastname: Ishima
authors.affiliation: Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Wagner
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Ji-Chun
authors.initials: JC
authors.lastname: Zhang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Chao
authors.initials: C
authors.lastname: Dong
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan;
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, CA 95616 bdhammock@ucdavis.edu hashimoto@faculty.chiba-u.jp.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; bdhammock@ucdavis.edu hashimoto@faculty.chiba-u.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054883:Oxylipins / Q000378:metabolism; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011922:Rats, Mutant Strains; D012919:Social Behavior; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics*
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D054883:Oxylipins; D010671:Phenylurea Compounds; D010880:Piperidines; D004851:Epoxide Hydrolases
keywords: brain-derived neurotrophic factor; depression; epoxyeicosatrienoic acid; resilience; soluble epoxide hydrolase