Antiepileptic drugs and apoptosis in the developing brain
Antiepileptic drugs and apoptosis in the developing brain
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DOI：
10.1111/j.1749-6632.2003.tb07517.x
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Ikonomidou, C
中科院分区：
文献类型：
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作者：
Bittigau, P;Sifringer, M;Ikonomidou, C
癫痫是年轻人中最常见的神经系统疾病。用于治疗儿童、婴儿和孕妇癫痫发作的抗癫痫药物（AEDs）可通过未知机制导致认知障碍、小头畸形和出生缺陷。我们测试了常见的抗癫痫药物是否会导致发育中的大鼠大脑神经退行性变。3- 30日龄大鼠接受苯妥英、苯巴比妥、地西泮、氯硝西泮、氨己烯酸或丙戊酸。大脑组织学检查显示，这些药物在大脑生长突增期导致发育中的大鼠大脑出现广泛且剂量依赖性的细胞凋亡神经变性。在与人类癫痫控制相关的血浆药物水平下触发凋亡性神经变性。抗癫痫药物导致神经营养因子的表达减少，ERK 1/2、RAF和AKT活性形式的浓度降低。β-雌二醇，刺激神经营养因子激活的通路，改善AED诱导的凋亡性神经变性。我们的研究结果提出了一种可能的机制来解释与人类出生前或出生后暴露于抗癫痫治疗相关的认知障碍和脑质量减少。
Epilepsy is the most common neurologic disorder in young humans. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects by unknown mechanisms. We tested whether common AEDs cause neurodegeneration in the developing rat brain. Rats aged 3-30days received phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, or valproic acid. Histologic examination of the brains revealed that these drugs cause widespread and dose-dependent apoptotic neurodegeneration in the developing rat brain during the brain growth spurt period. Apoptotic neurodegeneration was triggered at plasma drug levels relevant for seizure control in humans. Antiepileptic drugs lead to reduced expression of neurotrophins and decreased concentrations of the active forms of ERK1/2, RAF, and AKT. P-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorated AEDs-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with pre- or postnatal exposure of humans to antiepileptic therapy.