title: Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway.
abstract: Neurogenesis in the adult dentate gyrus (DG) is decreased in rodent models for mood disorders. Mood stabilizers including lithium (Li) and valproate (VPA) increase it. These increasing effects of Li and VPA on neurogenesis in adult DG are considered to be one of the therapeutic actions of Li and VPA, but their molecular mechanism remains unclear. We have already reported that Li recovers the inhibitory effects of dexamethasone (DEX), an agonist of glucocorticoid receptor, on the proliferation of adult rat DG-derived neural precursor cells (ADP) via GSK-3β and β-catenin pathway. Following it, here we investigated the mechanism underlying the recovery effects of VPA on DEX-induced decrease of ADP proliferation. VPA is an inhibitor of histone deacetylase (HDAC). However, Trichostatin A, a HDAC inhibitor, had no effect on ADP proliferation. In contrast, SB415286, a specific GSK-3β inhibitor, recovered DEX-induced decrease of ADP proliferation. In addition, quercetin (Que), a β-catenin pathway inhibitor, abolished such a recovery effect of VPA. Moreover, nuclear β-catenin and the expression of cyclin D1 were altered by DEX, VPA and Que like the proliferation. Moreover, VPA increased the phosphorylation of Ser(9), which is known as the inhibitory phosphorylation site of GSK-3β. These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser(9) on GSK-3β and following up-regulation of β-catenin pathway. Therefore, GSK-3β and β-catenin pathway might play a role in the increasing effects of VPA on neurogenesis on adult DG.
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: shuboku@med.hokudai.ac.jp.
authors.forename: Shuken
authors.initials: S
authors.lastname: Boku
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Pharmaceutical Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Pharmaceutical Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kato
authors.affiliation: Pharmaceutical Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takamura
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Omiya
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kitaichi
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kusumi
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D018891:Dentate Gyrus / Q000166:cytology*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018692:Antimanic Agents; C495268:Ctnnb1 protein, rat; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D051176:beta Catenin; D019938:Cyclin D1; D014635:Valproic Acid; D003907:Dexamethasone; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases
keywords: Glucocorticoid; Hippocampus; Mood disorder; Mood stabilizer; Neurogenesis