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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 investigate the effects of antiepileptic drugs (AEDs) on immature brain development at the blood concentration level. Methods The serum concentration of AEDs reached the steady state blood concentration of clinical treatment as the experimental dose. The healthy infant and adult SD rats were established as CNP, VP, VPA and topiramate TPM) experimental group and normal control group (18 rats each). AEDs were given to stomach for 5 weeks. Morris water maze test and shuttle box test were performed on the following day, 2 weeks and 1 month after drug withdrawal. On the day of discontinuation, the body weight, brain weight, hippocampus and frontal lobe tissue were examined by hematoxylin-eosin (HE), Nissl staining and electron microscopy. Results (1) In the shuttle box test on the next day and two weeks after withdrawal, the escape latency of CNP and PB group was significantly longer than that of the control group. The difference between CNP [(6.05 ± 2.04) s] and PB [(5.81 ± 1.75) s] and control group was still statistically significant [(4.75 ± 2.43) s, P < 0.01]. However, there was no difference between the AEDs group and the control group at 2 weeks after drug withdrawal. (2) In the Morris water maze test, the CNP and PB groups of young rats were erected on the following day, 2 weeks and 1 month after drug withdrawal Latencies were longer than the control group. However, there was no difference in the incubation period between two groups in adult rats (P <0.05). (2) The brain weight of CNP group (1.67 ± 0.04) g and (1.66 ± 0.04) ± 0.06) g]. (4) The neurons were extensively degenerated and necrotic. The number of nerve cells in the CNP group was (76.87 ± 18.60) / 200 times than that in the control group (72.60 ± 17.26) / 200 times of the PB group [(109.13 ± 33.73) / 200 times field of view, P <0.01]; (5) After 1 month of withdrawal, the ultrastructure of neurons in PB group was still abnormal. Conclusion Long-term use of PB, CNP can cause immature brain learning and memory function and histopathology continued abnormalities, PB of immature brain injury may not be easily restored.