title: A novel 2-decenoic acid thioester ameliorates corticosterone-induced depression- and anxiety-like behaviors and normalizes reduced hippocampal signal transduction in treated mice.
abstract: We characterized mice administered corticosterone (CORT) at a dose of 20 mg/kg for 3 weeks to determine their suitability as a model of mood disorders and found that the time immobilized in the tail suspension test was longer and the time spent in the open arms of the elevated plus-maze test was shorter than those of the vehicle-treated group, findings demonstrating that chronic CORT induced both depression-like and anxiety-like behaviors. Furthermore, the levels of phosphorylated extracellular signal-regulated kinase (pERK) 1/2 in the hippocampus and cerebral cortex were reduced in the CORT-treated group. Using this model, we investigated the protective effect of the ester, thioester, and amide compounds of 2-decenoic acid derivatives (termed compounds A, B, and C, respectively). The potency of the protective activity against the CORT-induced depression-like or anxiety-like behaviors and the reduction in pERK1/2 level were found to be in the following order: compound B > compound C > compound A. Therefore, we further investigated the therapeutic activity of only compound B, and its effect on depression-like behavior was observed after oral administration for 1 or 2 weeks, and its effect on anxiety-like behavior was observed after oral administration for 3 weeks. The ratios of phosphorylated ERK1/2, Akt, and cAMP-response element-binding protein to their respective nonphosphorylated forms were smaller in the CORT-treated group than in the vehicle-treated group; however, subsequent treatment with compound B at either 0.3 or 1.5 mg/kg significantly ameliorated this reduction. Compound B appeared to elicit intracellular signaling, similar to that elicited by brain-derived neurotrophic factor, and its mode of action was shown to be novel and different from that of fluvoxamine, a currently prescribed drug for mood disorders.
authors.affiliation: Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan.
authors.forename: Shoyo
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Laboratory of Pharmacognosy, Department of Bioactive Molecules, Gifu Pharmaceutical University Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan.
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.affiliation: Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Soumiya
authors.affiliation: Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukumitsu
authors.affiliation: Department of Pharmaceutical Pharmacology, Faculty of Pharmaceutical Sciences, Matsuyama University Bunkyo-cho 4-2, Matsuyama, Ehime, 790-8578, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University Daigaku-nishi 1-25-4, Gifu, 501-1196, Japan.
authors.forename: Shoei
authors.initials: S
authors.lastname: Furukawa
keywords: 2-decenoic acid thioester; anxiety-like behavior; corticosterone; depression-like behavior; extracellular signal-regulated kinase (ERK) 1/2; fluvoxamine