Department of Psychiatry, Faculty of Medicine, Juntendo University, Tokyo, Japan.
Department of Histology and Neuroanatomy, Tokyo Medical University, Tokyo, Japan.
Neuropsychopharmacol Rep. 2021 Jun;41(2):260-264. doi: 10.1002/npr2.12181. Epub 2021 May 5.
In pregnant women with epilepsy, it is essential to balance maternal safety and the potential teratogenicity of anticonvulsants. Recently, growing evidence has indicated that valproic acid (VPA) can produce postnatal congenital malformations and impair cognitive function. However, the mechanisms underlying cognitive dysfunction in long-term prognoses remain unclear.
Pregnant Wistar rats received daily intraperitoneal injections of VPA (200 mg/kg/day) from embryonic day 12.5 until birth. On postnatal day (PD) 149, the rats received an injection of bromodeoxyuridine (BrdU). On PD 150, the rats were subjected to the open field (OF), elevated plus-maze (EPM), and Y-maze tests. After behavioral testing, perfusion fixation was performed and the brain was dissected for immunohistochemistry.
A significant marked decrease was seen in the number of BrdU-positive cells in the dentate gyrus of offspring of VPA-treated dams compared to those of control. However, no significant differences in hyperactivity were found based on the results of the OF test among the offspring on PD 150 of 200 VPA-treated dams. In addition, no significant differences were seen in the EPM test.
The behavioral abnormality observed in young offspring of VPA-treated dams was not significantly different from that of controls in adult offspring on PD 150. However, compared with controls, the number of BrdU-positive cells in VPA-treated rats was halved. The findings suggest that the behavioral abnormality seems to improve as they grow, even if some structural abnormalities may remain in the central nervous system.
在患有癫痫的孕妇中，平衡母体安全性和抗癫痫药物的潜在致畸性至关重要。最近，越来越多的证据表明，丙戊酸（VPA）会导致产后先天性畸形并损害认知功能。然而，长期预后中认知功能障碍的机制仍不清楚。
从胚胎第 12.5 天开始，给怀孕的 Wistar 大鼠每天腹腔注射 VPA（200mg/kg/天），直到分娩。在产后第 149 天，大鼠接受溴脱氧尿苷（BrdU）注射。在产后第 150 天，大鼠接受旷场（OF）、高架十字迷宫（EPM）和 Y 迷宫测试。行为测试后，进行灌注固定并解剖大脑进行免疫组织化学分析。
与对照组相比，VPA 处理的母鼠后代齿状回中的 BrdU 阳性细胞数量明显减少。然而，在产后第 150 天的 OF 测试中，200 VPA 处理的母鼠后代的活动过度没有显著差异。此外，EPM 测试中也没有发现显著差异。
与对照组相比，VPA 处理的母鼠后代在产后第 150 天的成年后代中观察到的行为异常没有显著差异。然而，与对照组相比，VPA 处理的大鼠中 BrdU 阳性细胞的数量减少了一半。研究结果表明，即使中枢神经系统可能存在一些结构异常，行为异常似乎随着生长而改善。
