抗痫促智药物对认知功能障碍致痫大鼠海马细胞外信号调节激酶2及神经细胞黏附分子1表达的影响

Effect of anti-epileptic, nootropic drugs on the expression of ERK2 and NCAM1 in the hippocampus chan- ges on the epileptic rats with cognitive dysfunction

目的 探讨细胞外信号调节激酶2（ERK2）及神经细胞黏附分子1（NCAM1）在癫痫认知功能障碍中的作用及抗痫、促智药物对二者作用.方法 将120只Wistar大鼠分为对照组、致痫组和卡马西平组、奥卡西平组、茴拉西坦组、盐酸多奈哌齐组治疗30 d,对照组用生理盐水造模,其余5组用匹罗卡品诱导癫痫模型,将造模成功的大鼠给予上述成药物干预模型,大鼠的学习记忆能力通过Morris水迷宫实验测试,记录逃避潜伏期和原平台象限游泳时间；并用RT-PCR法检测NCAM1、ERK2在大鼠海马组织中的mRNA表达,免疫组化法检测大鼠海马组织中NCAM1和ERK2的蛋白表达.结果 定位航行试验中,与对照组大鼠逃避潜伏期相比,致痫组[（67.14±7.37）s]＞对照组[（35.78±4.84）s]（P＜0.01）,其中卡马西平组与盐酸多奈哌齐组与致痫组比较,卡马西平组[（81.23±9.46）s]＞致痫组[（67.14±7.37）s]（P＜0.01）,盐酸多奈哌齐组[（53.75±6.74）s]＜致痫组[（67.14±7.37）s]（P＜0.01）.各组ERK2蛋白表达及mRNA比较为：卡马西平组＜奥卡西平组＜致痫组＜茴拉西坦组＜多奈哌齐组＜对照组.与对照组比,多奈哌齐组＞对照组（P＜0.01）,茴拉西坦组＞对照组（P＜0.05）.结论 ERK2在癫痫发作30 d时在海马的表达水平下降,NCAM1则相反,ERK2活性的减低和NCAM1的过度表达可能是癫痫后认知功能损害的潜在机制.卡马西平能加重癫痫认知功能障碍程度,盐酸多奈哌齐可明显改善癫痫鼠的认知功能.

Objective To study the effect of anti-epileptic,nootropic drugs on the expression of NCAM and ERK2 in the hippocampus changes on the epileptic rats with cognitive dysfunction.Methods A total of 120Wistar rats were used.20 controls and 100 in which epilepticus with cognitive dysfunction were randomly assigned to 5 groups （n =20/group） that received daily treatments for 30 days with either （1） saline （epilepsy）,（2） carbamazine （traditional anti-epileptic）,（3） oxcarbazine （new anti-epileptic）,（4） aniracetam （brain protective）,or （5） donepezil （nootopic）.Spatial learning and memory were assessed with a Morris Water Maze （MWM）.Hippocampus tissue was assessed for NCAM1 and ERK-2 mRNAs by RT-PCR and proteins by immunochemistry.Results The mean escape latency of the place navigation test：EP group （（67.14 ± 7.37）s）was all higher than NS group （35.78 ± 4.84 s）and there was statistical significance （P 〈 0.01）,carbamazepine group （（81.23 ± 9.46）s） 〉 EP group（（67.14 ±7.37）s） 〉 donepezi group（（53.75 ±6.74） s） （P〈0.01）.Immunohistochemical and RT-PCR result：carbamazepine 〈 oxcarbazepine 〈 epilepsy 〈 aniracetam 〈 donepezi group.Compared with control group,donepezil group 〉 control group （P 〈 0.01）,aniracetam group 〉 control group （P 〈 0.05）.Conclusion ERK-2 expression is decreased and NCAM 1 expression is increased in the hippocampus in the epileptic rats.Thus,both are involved in cognitive dysfunction.Carbamazepine aggravates cognitive dysfunction,whereas donepezil improves cognitive dysfunction associated with epilepsy.