Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
La Trobe Centre for Sport and Exercise Medicine Research, School of Allied Health, Human Services, and Sport, La Trobe University, Bundoora, Victoria, Australia.
Epilepsia. 2020 Jun;61(6):1291-1300. doi: 10.1111/epi.16536. Epub 2020 May 16.
Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.
We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non-Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same-strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements.
VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls of all three strains (P < .0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%).
Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug-induced birth defects.
丙戊酸钠（VPA）是治疗遗传性全面性癫痫（GGE）患者最有效的抗癫痫药物，也是一种有效的人类致畸剂，会增加多种先天性畸形的风险，包括脊柱裂。其致畸机制尚不清楚，但可能涉及遗传风险因素。本研究旨在建立 VPA 诱导出生缺陷的动物模型。
我们使用了三种不同的大鼠品系：来自斯特拉斯堡的遗传性癫痫缺失大鼠（GAERS），一种具有缺失性癫痫发作的 GGE 模型；非癫痫对照（NEC）；以及非癫痫的 Wistar 大鼠。雌性大鼠在受孕前 2 周内食用标准饲料或混合在标准饲料中的 VPA（20g/kg 食物），然后与同系雄性大鼠交配。治疗在整个孕期持续进行。在妊娠第 21 天通过剖宫产取出胎儿，并检查出生缺陷，包括外部评估和脊柱测量。
与所有三种品系的对照组相比，VPA 暴露的幼鼠体重、体长和全身发育明显减少（P<0.0001）。妊娠期 VPA 处理改变了椎内距离，并导致 T11 胸椎区和 C2 尾椎区之间的椎弓发育不全，大多数幼鼠（GAERS，100%；NEC，95%；Wistar，80%）比对照组更频繁（9%、13%、19%）。
妊娠期 VPA 处理在三种大鼠品系中导致相似的发育和形态异常，包括一种具有 GGE 的大鼠，表明癫痫的遗传基础对 VPA 诱导的出生缺陷没有显著贡献。该模型可用于未来研究，以探讨抗癫痫药物诱导的出生缺陷发病机制中涉及的机制。
