Abstract
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.
概要
目的
丙戊酸是一种用于治疗癫痫发作的药物, 可引起 成人和儿童的空间记忆障碍。 海马的神经发生与 学习能力密切相关, 而丙戊酸可抑制该区域的神 经发生, 从而导致空间记忆障碍。 我们已有动物 模型证明丙戊酸能显著损害海马-空间工作记 忆, 并抑制齿状回亚颗粒区域中的神经元生成。 既往临床病例报道指出患者在停用丙戊酸治疗 后记忆能力有所改善。 因此, 本实验研究停用丙 戊酸治疗后两个时间点的空间记忆和海马神经 发生的恢复情况。
创新点
研究了停用丙戊酸后的空间记忆恢复的时间进程 以及与海马神经发生变化之间的关系。
方法
雄性Wistar 大鼠每天两次腹膜内注射0.9%生理 盐水或丙戊酸(300 mg/kg), 持续10 天。 在药物 治疗结束后第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情况;并使用免疫印 迹法(western immunoblotting)测量脑源性神经 营养因子(BDNF)和Notch1 的水平。
结论
药物治疗结束后第1 天和第30 天大鼠的空间工作 记忆有受损, 但在第45 天时, 恢复到正常水平。 细胞增殖在第30 天和第45 天时增加至正常水 平。 神经发生的两种标志物(BDNF 和Notch1) 在第45 天时恢复到正常水平。 这些结果表明了 记忆能力的恢复发生在停用丙戊酸6 周内, 并且 该种效应发生在海马神经发生恢复至正常水平 后。
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Project supported by the Invitation Research of the Faculty of Medicine, Neuroscience Research and Development Group, Khon Kaen University, Thailand (No. I54119)
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Pannangrong, W., Sirichoat, A., Wongsiri, T. et al. Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis. J. Zhejiang Univ. Sci. B 20, 253–263 (2019). https://doi.org/10.1631/jzus.B1800340
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DOI: https://doi.org/10.1631/jzus.B1800340