title: Effects of AS2586114, a soluble epoxide hydrolase inhibitor, on hyperlocomotion and prepulse inhibition deficits in mice after administration of phencyclidine.
abstract: Accumulating evidence suggests that soluble epoxide hydrolase (sEH) plays a key role in controlling levels of lipid signaling molecules, and that the potent sEH inhibitors may be potential therapeutic drugs for a number of diseases associated with metabolism of epoxyeicosatrienoic acids (EETs). This study was undertaken to examine whether the potent sEH inhibitor AS2586114 could attenuate behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition (PPI) deficits) in male ddY mice after a single administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP). A single oral administration of AS2586114 (10, 30, or 100 mg/kg) attenuated the hyperlocomotion in mice after the administration of PCP (3.0 mg/kg, s.c.), in a dose dependent manner. Furthermore, a single oral administration of AS2586114 (10, 30, or 100 mg/kg) improved the PPI deficits in mice after the administration of PCP (3.0 mg/kg, s.c.), in a dose dependent manner. In addition, the atypical antipsychotic drug clozapine (10 mg/kg, p.o.) significantly attenuated hyperlocomotion and PPI deficits after the administration of PCP (3.0 mg/kg, s.c.). In conclusion, this study suggests that AS2586114 may have antipsychotic activity in PCP models of schizophrenia. Therefore, it is likely that the sEH inhibitors may be potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tamaki
authors.initials: T
authors.lastname: Ishima
authors.forename: Ji-Chun
authors.initials: JC
authors.lastname: Zhang
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C000589444:3-cyclopropyl-4-(4-(2-(((6,6-dimethylbicyclo(3.1.1)heptan-2-yl)methyl)amino)-2-oxoethyl)piperidin-1-yl)benzoic acid; D001565:Benzoates; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D004851:Epoxide Hydrolases; D010622:Phencyclidine
keywords: Antipsychotic drug; Epoxyeicosatrienoic acids; Phencyclidine; Prepulse inhibition; Soluble epoxide hydrolase