摘要
目的探讨抗癫癎药物(AEDs)在治疗血浓度下对未成熟脑发育的影响。方法以AEDs 血浓度达到临床治疗稳态血浓度为实验剂量,设立健康幼鼠及成年 SD 大鼠氯硝西泮(CNP)、苯巴比妥(PB)、丙戊酸(VPA)、托吡酯(TPM)实验组及正常对照组(各18只)。AEDs 灌胃5周,于停药后次日、2周及1个月末,行 Morris 水迷宫及穿梭箱测试。停药当天记录体重、脑重,海马及额叶组织行苏木素-伊红(HE)、尼氏染色及电镜观察。结果 (1)停药后次日及2周的穿梭箱实验,幼鼠CNP 和 PB 组逃避潜伏期明显长于对照组。即使停药后1个月,幼鼠 CNP[(6.05±2.04)s]及 PB 组[(5.81±1.75)s]与对照组的差异仍有统计学意义[(4.75±2.43)s,P<0.01]。而停药后2周,成年鼠各 AEDs 组与对照组已无差异;(2)Morris 水迷宫实验,分别于停药后次日、2周及1个月,幼鼠 CNP和 PB 组登平台潜伏期均长于对照组。而成年鼠各组登平台潜伏期于停药后2周已无差异;(3)幼鼠CNP 组脑重(1.67±0.04)g,PB 组脑重(1.66±0.04)g,较对照[(1.75±0.06)g]轻;(4)神经元广泛变性坏死,神经细胞数[CNP 组为(76.87±18.60)个/200倍视野,PB 组(72.60±17.26)个/200倍视野]较对照少[(109.13±33.73)个/200倍视野,P<0.01];(5)停药1个月后,PB 组幼鼠神经元超微结构仍异常。结论长期服用 PB、CNP 可引起未成熟脑学习记忆功能及脑组织病理学持续异常,PB对未成熟脑的损伤存在可能是不易恢复的。
Objective To explore the different influence of antiepileptic drugs （AEDs） at therapeutic levels to the maturation of brain. Methods 180 healthy Sprague-Dawley （SD） rats were divided into infant and adult group. Each age group was administered with PB, CNP, VPA, TPM or normal saline respectively in persistent 5 weeks. The steady-state plasma concentrations of AEDs at the experimental dosage were coincided with the range of clinical therapeutic concentrations. After AEDs withdrawed, the effects of AEDs on cognitive function were assessed by Morris water maze and two-way shuttle box at different time points. Body and brain weight were got immediately when the rats were sacrificed. Histological changes of brain were observed by HE staining, Nissl staining and transmission electron microscopy. Results （ 1 ） For immature rats, 1 day or 14 days after AEDs withdrawed, there were significant differences between groups exposed to PB or CNP and control group in escape response latency （ERL） in the two-way shuttle box. Even after one month ERLs of immature rats receiving CNP （ （6. 05 ± 2. 04） s） or PB （ （5.81 ± 1.75） s） were still longer than that of untreated controls （（4.75 ±2.43） s, P 〈0.01）. As for adult groups, these differences between AEDs-treated groups and control group in ERL were all disappeared after two weeks. （2） In the Morris water maze, immature rats treated with CNP or PB always performed worse than untreated controls at different time points. However, there were no differences among adult groups after two weeks. （3） Remarkable reduction of brain weight was only observed in immature rats exposed to CNP （（1.67±0.04） g） or PB （（1.66±0.04） g） compared with control group （（1.75 ±0.06） g, P〈 0. 01 ）. （4） Significant neuredegeneration, neuronal necrosis and decrease in the number of neurons were observed in immature rats exposed to PB and CNP compared with controls. （5） Even 30 days after drug withdrawed, significant ultrastructural changes of neurons also can be seen in PB-treated immature rats.Conclusions Even at therapeutic level, chronic treatment with PB and CNP will result in persistent cognitive impairment and significant brain damage to immature rats.
出处
《中华神经科杂志》
CAS
CSCD
北大核心
2007年第3期157-161,共5页
Chinese Journal of Neurology
关键词
抗惊厥药
脑
迷宫学习
记忆
体重
Anticonvulsants
Brain
Maze learning
Memory
Bodyweight
