Center for Neuroscience and Regenerative Medicine, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States.
Neurosci Lett. 2011 Aug 18;500(3):202-6. doi: 10.1016/j.neulet.2011.06.037. Epub 2011 Jun 29.
The mood stabilizer valproic acid (VPA) decreases neural progenitor proliferation and promotes neurogenesis in the adult hippocampus. However, the effects of VPA on progenitor cells in the adult subventricular zone (SVZ) are not as well characterized. Here we report VPA blocks neurosphere formation and inhibits DNA synthesis in cultured NSCs from the SVZ of adult mice. Inhibition of DNA synthesis is associated with the up-regulation of the differentiation transcription factors Egr1 and Neurod1 and down-regulation of transcription factors associated with "stemness". Co-treatment of VPA with the mood stabilizer lithium antagonizes the anti-proliferative effects of VPA on adult NSCs and abolishes VPA activation of Egr1. Co-treatment of VPA with the MEK1/2 inhibitor PD980589 similarly abolishes Egr1 activation consistent with VPA activation and lithium antagonism of MEK-ERK signaling in adult NSCs. However, Western blot reveals VPA significantly suppresses ERK2 phosphorylation in adult NSCs grown in proliferating culture conditions and that lithium co-treatment does not attenuate this effect. Combined the data indicate VPA inhibition of adult NSC proliferation and activation of Egr1 by VPA, along with the antagonism of these effects by lithium, are the effects of cumulative changes in multiple signaling pathways and are not attributable to a common kinase target.
心境稳定剂丙戊酸（VPA）可减少成年海马中的神经祖细胞增殖并促进神经发生。然而，VPA 对成年侧脑室下区（SVZ）祖细胞的影响尚未得到很好的描述。在这里，我们报告 VPA 可阻断培养的成年小鼠 SVZ 神经球的形成并抑制 DNA 合成。DNA 合成的抑制与分化转录因子 Egr1 和 Neurod1 的上调以及与“干性”相关的转录因子的下调有关。VPA 与心境稳定剂锂共同处理可拮抗 VPA 对成年 NSCs 的增殖抑制作用，并消除 VPA 对 Egr1 的激活。VPA 与 MEK1/2 抑制剂 PD980589 的共同处理也同样消除了 Egr1 的激活，这与 VPA 激活以及在成年 NSCs 中锂拮抗 MEK-ERK 信号通路一致。然而，Western blot 显示 VPA 可显著抑制在增殖培养条件下生长的成年 NSCs 中 ERK2 的磷酸化，而锂共同处理并不能减弱这种作用。综合这些数据表明，VPA 抑制成年 NSC 的增殖并激活 Egr1，而锂拮抗这些作用，是多种信号通路累积变化的结果，而不是归因于共同的激酶靶标。
