Objective: It is well documented that epilepsy can increase neurogenesis in certain brain regions and cause behavioral alternations in patients and different epileptic animal models. A series of experimental studies have demonstrated that neurogenesis is regulated by various factors including glucocorticoid (CORT), which can reduce neurogenesis. Most of studies in animal have been focused on adulthood stage, while the effect of recurrent seizures to immature brain in neonatal period has not been well established. This study was designed to investigate how the recurrent seizures occurred in the neonatal period affected the immature brain and how CORT regulated neurogenesis in immature animals.
Methods: Neonatal rats were subjected to 3 pilocarpine-induced seizures from postnatal day 1 to day 7. Then neurogenesis at different postnatal ages (i.e. P8, P12, P22, P50) was observed. Behavioral performance was tested when the rats were mature (P40), and plasma CORT levels following recurrent seizures were simultaneously monitored.
Results: Rats with neonatal seizures had a significant reduction in the number of Bromodeoxyuridine (BrdU) labeled cells in the dentate gyrus compared with the control groups when the animals were euthanized on P8 or P12 (P<0.05); whereas there was no difference between the two groups on P22. Until P50, rats with neonatal seizures had increased number of BrdU-labeled cells compared with the control group (P<0.05). In Morris water maze task, pilocarpine-treated rats were significantly slower than the control rats at the first and second day, and there were no differences at other days. In probe trial, there was no significant difference in time spent in the goal quadrant between the two groups. Endocrine studies showed a correlation between the number of BrdU positive cells and the CORT level. Sustained increase in circulating CORT levels was observed following neonatal seizures on P8 and P12.
Conclusion: Neonatal recurrent seizures can biphasely modulate neurogenesis over different time windows with a down-regulation at early time and up-regulation afterwards, cause persistent deficits in cognitive functions of adults, and increase the circulating CORT levels. CORT levels are related with the morphological and behavioral consequences of recurrent seizures.
目的: 探讨新生期大鼠反复痫性发作后的形态学, 行为学以及糖皮质激素水平的变化。
方法: 64只出生后一天的 Wistar 大鼠随机分为惊厥组40只和对照组24只。 惊厥组的新生鼠在出生后1天(P1)、 4天(P4)、 7天(P7)给予腹腔注射匹罗卡品, 制备新生鼠癫痫模型, 对照组的新生鼠腹腔注射生理盐水。 惊厥组分别在第3次致痫后在即刻(I组)、 第4天(I 组)、 第 14 天(III组)、 第42天(IV组)四个时间点处死, 各时间点设相应对照组, 处死前36 h惊厥组和对照组的大鼠腹腔注射BrdU。 所有大鼠处死前均取血检测糖皮质激素。 第IV组从P40开始进行Morris水迷宫试验。
结果: 新生鼠3次发作后即刻和第4天与相应日龄对照组相比, 状回BrdU阳性细胞数明显减少(P < 0.05), 而癫痫发作后14天和42天BrdU阳性细胞数增加, 但发作后14天差异无统计学意义(P > 0.05)。 在4天的Morris水迷宫试验中, 匹罗卡品处理组大鼠到达平台的时间均长于对照组, 但是只有第1天和第2天有统计学意义(P < 0.05)。 检测结果表明高水平的糖皮质激素一直持续到发作后第4天, 糖皮质激素水平与BrdU阳性细胞数呈负相关。
结论: 新生大鼠反复痫性发作会造成早期神经发生减少, 而后期神经发生增加; 造成大鼠成年后认知功能缺陷; 造成糖皮质激素水平增高, 这与痫性大鼠形态学和行为学方面的改变有关。