Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3尾 and 尾-catenin pathway

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• 作者：Shuken Boku ; Shin Nakagawa ; Takahiro Masuda ; Hiroyuki Nishikawa ; Akiko Kato ; Naoki Takamura ; Yuki Omiya ; Yuji Kitaichi ; Takeshi Inoue ; Ichiro Kusumi
• 关键词：Neurogenesis ; Glucocorticoid ; Mood disorder ; Mood stabilizer ; Hippocampus
• 刊名：European Journal of Pharmacology
• 出版年：15 January, 2014
• 年：2014
• 卷：723
• 期：Complete
• 页码：425-430
• 全文大小：1093 K

文摘

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-3尾 and 尾-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-3尾 inhibitor, recovered DEX-induced decrease of ADP proliferation. In addition, quercetin (Que), a 尾-catenin pathway inhibitor, abolished such a recovery effect of VPA. Moreover, nuclear 尾-catenin and the expression of cyclin D1 were altered by DEX, VPA and Que like the proliferation. Moreover, VPA increased the phosphorylation of Ser⁹, which is known as the inhibitory phosphorylation site of GSK-3尾. 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 Ser⁹ on GSK-3尾 and following up-regulation of 尾-catenin pathway. Therefore, GSK-3尾 and 尾-catenin pathway might play a role in the increasing effects of VPA on neurogenesis on adult DG.