Podgorac Jelena, Pešić Vesna, Pavković Željko, Martać Ljiljana, Kanazir Selma, Filipović Ljupka, Sekulić Slobodan
Department of Neurophysiology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
Department of Neurobiology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
Behav Brain Res. 2016 Sep 15;311:99-109. doi: 10.1016/j.bbr.2016.05.023. Epub 2016 May 14.
Clinical research has identified developmental delay and physical malformations in children prenatally exposed to the antiepileptic drug (AED) valproic acid (VPA). However, the early signs of neurodevelopmental deficits, their evolution during postnatal development and growth, and the dose effects of VPA are not well understood. The present study aimed to examine the influence of maternal exposure to a wide dose range (50, 100, 200 and 400mg/kg/day) of VPA during breeding and gestation on early physical and neuromotor development in mice offspring. Body weight gain, eye opening, the surface righting reflex (SRR) and tail suspension test (TST) were examined in the offspring at postnatal days 5, 10 and 15. We observed that: (1) all tested doses of VPA reduced the body weight of the offspring and the timing of eye opening; (2) offspring exposed to VPA displayed immature forms of righting and required more time to complete the SRR; (3) latency for the first immobilization in the TST is shorter in offspring exposed to higher doses of VPA; however, mice in all groups exposed to VPA exhibited atypical changes in this parameter during the examined period of maturation; (4) irregularities in swinging and curling activities were observed in animals exposed to higher doses of VPA. This study points to delayed somatic development and postponed maturation of the motor system in all of the offspring prenatally exposed to VPA, with stronger effects observed at higher doses. The results implicate that the strategy of continuous monitoring of general health and achievements in motor milestones during the early postnatal development in prenatally VPA-exposed offspring, irrespectively of the dose applied, could help to recognize early developmental irregularities.
临床研究已确定，产前接触抗癫痫药物（AED）丙戊酸（VPA）的儿童存在发育迟缓及身体畸形。然而，神经发育缺陷的早期迹象、其在出生后发育和成长过程中的演变以及VPA的剂量效应尚不清楚。本研究旨在探讨母鼠在繁殖和妊娠期接触宽剂量范围（50、100、200和400mg/kg/天）的VPA对小鼠后代早期身体和神经运动发育的影响。在出生后第5、10和15天对后代的体重增加、睁眼情况、表面翻正反射（SRR）和悬尾试验（TST）进行了检测。我们观察到：（1）所有测试剂量的VPA均降低了后代的体重并延迟了睁眼时间；（2）接触VPA的后代表现出不成熟的翻正形式，完成SRR所需时间更长；（3）在TST中，接触较高剂量VPA的后代首次静止不动的潜伏期较短；然而，在整个检测的成熟期间，所有接触VPA的组中的小鼠在该参数上均表现出非典型变化；（4）在接触较高剂量VPA的动物中观察到摆动和卷曲活动不规则。本研究指出，产前接触VPA的所有后代均出现身体发育延迟和运动系统成熟推迟，且在较高剂量下观察到的影响更强。结果表明，对产前接触VPA的后代在出生后早期发育期间持续监测总体健康状况和运动里程碑成就的策略，无论应用的剂量如何，都有助于识别早期发育异常。
