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Effects of repeated brief seizures and antiepileptic drugs in the developing rat brain.

机译：在发育中的大鼠脑中反复短暂发作和抗癫痫药的作用。

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摘要

Antiepileptic drugs (AEDs) induce apoptotic neuronal death in specific regions of rat brain during the first two postnatal weeks; this developmental neurotoxicity may contribute to adverse behavioral outcomes. In this project, four studies examined the impact of seizures and/or AEDs or AED combinations on cell survival in the immature brain. (1) This study tested the hypothesis that repeated seizures will increase basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and/or brain-derived neurotrophic factor (BDNF) in specific brain areas in the neonatal period. Chronic seizures induced by electroconvulsive shock (ECS) did not change trophic factor protein levels in the 1st postnatal week, increased BDNF during the 2nd postnatal week, and increased both BDNF and FGF-2 during the 3rd postnatal week. These data contrast with seizure-induced upregulation of trophic factors in adults. (2) To identify AEDs with minimal risk of neurotoxicity in the developing brain, the pro-apoptotic effects of carbamazepine (CBZ), topiramate (TPM), and levetiracetam (LEV), alone or combined with phenytoin, were evaluated in several brain areas. CBZ (50mg/kg) and TPM (20--80mg/kg) did not induce cell death when given alone, but exacerbated phenytoin-induced apoptosis. LEV (250--1000mg/kg) neither induced apoptosis nor exacerbated apoptosis induced by phenytoin. LEV (250mg/kg) plus CBZ (50mg/kg) was the only combination identified that did not induce apoptosis. The latter drugs may be especially promising candidates for therapy of women during pregnancy, and for pre-term and neonatal infants. (3) The impact of pre-exposure to repeated seizures on drug-induced neuronal apoptosis was examined in the first postnatal week. Pre-exposure to 3 days of ECS treatment did not affect apoptosis induced by valproate, phenobarbital or phenytoin. However, ECS pre-exposure significantly attenuated neuronal death induced by the glutamate antagonist, MK801. These data suggest that ECS can be neuroprotective, depending upon the mechanism by which apoptotic cell death is induced. (4) Pilot studies of long-term behavioral effects of neonatal seizures or neurodevelopmental apoptosis were initiated. Rats exposed to ECS or MK801 as neonates were tested at PD30 and PD60 in several behavioral tasks; tests of spatial novelty and of anxiety appeared to be especially sensitive to changes induced by the neonatal treatments.
机译：抗癫痫药（AED）在出生后的前两周会诱导大鼠大脑特定区域的凋亡性神经元死亡；这种发育性神经毒性可能会导致不良的行为结果。在该项目中，四项研究检查了癫痫发作和/或AED或AED组合对未成熟大脑细胞存活的影响。 （1）这项研究验证了这样的假设：反复发作会在新生儿期的特定大脑区域增加碱性成纤维细胞生长因子（FGF-2），神经生长因子（NGF）和/或脑源性神经营养因子（BDNF）。惊厥性电惊厥（ECS）诱发的慢性癫痫发作在产后第1周未改变营养因子蛋白水平，在产后第2周未升高BDNF，在产后第3周均升高BDNF和FGF-2。这些数据与癫痫引起的成年人营养因子上调形成鲜明对比。 （2）为了确定在发育中的大脑中神经毒性风险最小的AED，单独或与苯妥英钠联用的卡马西平（CBZ），托吡酯（TPM）和左乙拉西坦（LEV）的促凋亡作用被评估。单独服用CBZ（50mg / kg）和TPM（20--80mg / kg）不会诱导细胞死亡，但是会加剧苯妥英钠诱导的细胞凋亡。 LEV（250--1000mg / kg）既不诱导苯妥英诱导的细胞凋亡也不加剧苯妥英诱导的细胞凋亡。 LEV（250mg / kg）加CBZ（50mg / kg）是确定的唯一不诱导凋亡的组合。后一种药物可能是孕妇治疗孕妇以及早产儿和新生儿的特别有前途的候选药物。 （3）在出生后的第一个星期检查了暴露前反复发作对药物诱导的神经元凋亡的影响。暴露前3天的ECS治疗不会影响丙戊酸盐，苯巴比妥或苯妥英钠诱导的细胞凋亡。但是，ECS暴露前能明显减轻由谷氨酸拮抗剂MK801诱导的神经元死亡。这些数据表明，ECS可能具有神经保护作用，具体取决于诱导凋亡细胞死亡的机制。 （4）开始了对新生儿癫痫发作或神经发育凋亡的长期行为影响的试验研究。暴露于ECS或MK801的新生大鼠在PD30和PD60进行了多种行为任务测试；空间新颖性和焦虑性测试似乎对新生儿治疗引起的变化特别敏感。

著录项

  • 作者

    Kim, Jinsook.;

  • 作者单位

    Georgetown University Medical Center.;

  • 授予单位 Georgetown University Medical Center.;
  • 学科 Biology Neuroscience.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 238 p.
  • 总页数 238
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;药理学;
  • 关键词

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