Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
J Zhejiang Univ Sci B. 2019;20(3):253-263. doi: 10.1631/jzus.B1800340.
Valproic acid (VPA), an agent that is used to treat epileptic seizures, can cause spatial memory impairment in adults and children. This effect is thought to be due to the ability of VPA to inhibit neurogenesis in the hippocampus, which is required for learning. We have previously used an animal model to show that VPA significantly impairs hippocampal-spatial working memory and inhibits neuronal generation in the sub-granular zone of the dentate gyrus. As there are patient reports of improvements in memory after discontinuing VPA treatment, the present study investigated the recovery of both spatial memory and hippocampal neurogenesis at two time points after withdrawal of VPA. Male Wistar rats were given intraperitoneal injections of 0.9% normal saline or VPA (300 mg/kg) twice a day for 10 d. At 1, 30, or 45 d after the drug treatment, the novel object location (NOL) test was used to examine spatial memory; hippocampal cell division was counted using Ki67 immunohistochemistry, and levels of brain-derived neurotrophic factor (BDNF) and Notch1 were measured using western immunoblotting. Spatial working memory was impaired 1 and 30 d after the final administration, but was restored to control levels by 45 d. Cell proliferation had increased to control levels at 30 and 45 d. Both markers of neurogenesis (BDNF and Notch1 levels) had returned to control levels at 45 d. These results demonstrate that memory recovery occurs over a period of six weeks after discontinuing VPA treatment and is preceded by a return of hippocampal neurogenesis to control levels.
丙戊酸（VPA）是一种用于治疗癫痫发作的药物，它可以导致成人和儿童的空间记忆损伤。这种作用被认为是由于 VPA 能够抑制海马中的神经发生，而神经发生是学习所必需的。我们之前使用动物模型表明，VPA 显著损害了海马空间工作记忆，并抑制了齿状回颗粒下区的神经元生成。由于有患者报告在停止 VPA 治疗后记忆力有所改善，因此本研究在 VPA 停药后两个时间点调查了空间记忆和海马神经发生的恢复情况。雄性 Wistar 大鼠每天两次腹膜内注射 0.9%生理盐水或 VPA（300mg/kg），连续 10 天。在药物治疗后 1、30 或 45 天，使用新物体位置（NOL）测试来检查空间记忆；使用 Ki67 免疫组织化学计数海马细胞分裂，并使用 Western 免疫印迹测量脑源性神经营养因子（BDNF）和 Notch1 水平。在最后一次给药后 1 和 30 天，空间工作记忆受损，但在 45 天恢复到对照水平。细胞增殖在 30 和 45 天已恢复到对照水平。两种神经发生标志物（BDNF 和 Notch1 水平）均在 45 天恢复到对照水平。这些结果表明，在停止 VPA 治疗后六周内记忆恢复发生，并且在海马神经发生恢复到对照水平之前发生。
