[1]徐晓科,蔡方成,宋艳,等.常用抗惊厥治疗方案对新生鼠脑发育的影响[J].第三军医大学学报,2010,32(18):1981-1985.
 Xu Xiaoke,Cai Fangcheng,Song Yan,et al.Coventional anticonvulsant regimens induce brain damage in newborn rats[J].J Third Mil Med Univ,2010,32(18):1981-1985.
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常用抗惊厥治疗方案对新生鼠脑发育的影响(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
32卷
期数:
2010年第18期
页码:
1981-1985
栏目:
论著
出版日期:
2010-09-30

文章信息/Info

Title:
Coventional anticonvulsant regimens induce brain damage in newborn rats
作者:
徐晓科蔡方成宋艳李思秀
重庆医科大学附属儿童医院神经电生理中心
Author(s):
Xu Xiaoke Cai Fangcheng Song Yan Li Sixiu
Center of Neurological Electrophysiology, Children’s Hospital, Chongqing Medical University, Chongqing, 400014, China
关键词:
抗惊厥药临床方案脑损伤动物 新生大鼠
Keywords:
anticonvulsantsclinical protocolsbrain injuries animals newborn rats
分类号:
R720.597; R322.81; R339.3
文献标志码:
A
摘要:
目的  探讨临床常用的新生儿惊厥治疗方案中单用尤其联合使用传统抗惊厥药物对新生鼠脑发育的影响。 方法  以临床剂量换算大鼠用药剂量,新生7 d(P7)大鼠120只分为苯巴比妥(phenobarbital,PB)、地西泮(diazepam,DZP)、苯妥英(phenytoin,PHT)、苯巴比妥联合地西泮(PB+DZP)、苯巴比妥联合苯妥英(PB+PHT)和正常对照(给予等量生理盐水)共6组, 每组各20只。分别进行行为学(每组10只)及组织学观测(每组10只)。给药后24 h(P8)检测急性期脑损伤:ELISA法测定血清神经元特异性烯醇化酶(neuron-specific enolase,NSE)含量,免疫组化检测Bax、Bcl-2蛋白表达;原位末端标记法(TUNEL)检测凋亡细胞。P24行Morris水迷宫实验,HE、尼氏染色观察病理改变。 结果 PB、PHT、PB+DZP、PB+PHT组血清NSE浓度较正常对照组显著增高,分别高出52.48%、67.02%、152。48%和175.53%(P<0.01);PB+DZP和PB+PHT组分别高出PB单药65.58%和80.20% (P<0.01)。PB+PHT组Bcl-2蛋白表达较正常对照组显著降低(P<0.05),各用药组Bax蛋白的表达显著强于正常对照组(P<0.05);PB、DZP、PHT组海马下托TUNEL染色阳性细胞数较正常对照组(14.86±5.40)分别增加4.74倍、3.27倍、5.44倍 (P<0.01);PB+DZP和PB+PHT组分别高出PB组1.31倍和1.47倍(P<0.01)。Morris水迷宫实验,单药组PB、DZP组和正常对照组间差异无统计学差异(P>0.05),PHT组仅穿越平台的次数较正常对照组少,但其寻台潜伏期与对照组差异无显著性;联合用药组平均寻台潜伏期较正常对照组显著延长(P<0.01),且穿越平台次数较正常对照组减少,差异有统计学意义(P<0.01) 。P30幼鼠尼氏体染色400倍光镜下海马下托部神经元计数,与正常对照组(82.80±14.44)比较,PHT组、PB+DZP组、PB+PHT组的神经细胞数量分别减少22.6%、23.8%、31.3%(P<0。01)。 结论 单用PB、DZP、PHT能引起不同程度的急性期脑损伤,其脑损伤随3周生长发育得到恢复;PB+DZP、PB+PHT联合用药,其脑损伤更为严重,对发育脑造成长期的学习记忆损害。
Abstract:
Objective   To investigate the effect of conventional treatment, especially with multidrug, for neonatal seizure on rat brain development.  Methods   A total of 120 7-day-old rats were divided into 6 treatment groups (n=20). Each group was treated with following conventional seizure drugs at a dose determined according to clinical neonatal baby doses, Phenobarbital (PB), Diazepam (DZP), Phenytoin (PHT), Phenobarbital in combination with Diazepam (PB+DZP), Phenobarbital in combination with Phenytoin (PB+PHT) or normal saline respectively by intraperitoneal injection(i.p). In 24 h later, plasma neuron-specific enolase (NSE) was determined by ELISA. Expression levels of apoptosisrelated proteins Bax and Bcl-2 in the brain neurocytes was detected by immunohistochemistry. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL). The effects of anticonvulsant drugs on cognitive function were assessed by Morris water maze. Histological changes of brain were observed by HE and Nissl staining.  Results  The concentration of plasma NSE exposed to PB, PHT, PB+DZP and PB+PHT was significantly increased by 52.48%, 67.02%, 152.48% and 175.53% respectively compared with controls [(0.282±0.1340) ng/L] (P<0.01), and the NSE exposed to PB+DZP and PB+PHT significantly was increased by 65.58% and 80.20% respectively compared with PB group (P<0.01). The expression of Bax protein was significantly elevated in all treatment groups compared with controls (P<0.05). But the expression Bcl-2 protein was significantly decreased in the PB+PHT group compared to control (P<0.05). While the number of TUNEL positive cells in the subicular complex exposed to PB, DZP and PHT was significantly increased by 4.74-fold, 3.27-fold and 5.44-fold respectively compared with control group (P<0.01), moreover, exposure to PB+DZP and PB+PHT were significantly increased by 1.31-fold and 1.47-fold compared with PB group (P<0.01). The rats treated with PB+DZP and PB+PHT always performed worse than controls in Morris water maze. Significant decrease in the number of neurons were observed in subicular complex of rats at postnatal day 30 exposed to PHT, PB+DZP and PB+PHT compared with controls.  Conclusion  PB, DZP and PHT treatment for neonatal seizure can cause acute brain damage. The brain damage will get partly recovered in 3 weeks later, and will not cause cognitive impairment. However, PB+DZP and PB+PHT administration result in more sever brain damage, and even persistent cognitive impairment in neonatal rats.

参考文献/References:

徐晓科, 蔡方成, 宋艳, 等. 常用抗惊厥治疗方案对新生鼠脑发育的影响[J].第三军医大学学报,2010,32(18):1981-1985.

更新日期/Last Update: 2010-09-25