Teratogenic Effects of Topiramate in a Zebrafish Model

托吡酯在斑马鱼模型中的致畸作用

托吡酯（Topiramate）为天然单糖基右旋果糖硫化物。体外研究证实，本品抗癫痫作用的机制可能是：①选择性阻断电压依赖的钠通道，以限制持续的反复放电；②作用于γ-氨基丁酸受体，增强γ-氨基丁酸的神经抑制作用；③作用于谷氨酸受体，拮抗海人酸/AMPA性谷氨酸受体，降低谷氨酸介导的神经兴奋作用。

Abstract: Topiramate is commonly used for treating epilepsy in both children and adults.
Recent clinical data suggests that administration of topiramate to women during pregnancy increases the risk of oral clefts in their offspring. To better understand the potential effects of topiramate, we dosed adult female zebrafish with topiramate, and investigated the altered morphologies in adult females and their offspring. It showed that topiramate-treated female fish had reduced oocyte maturation, and the survival rates of their offspring were seriously decreased during embryogenesis.In addition, around 23% of offspring displayed cartilage malformation in the craniofacial area, such as loss of ceratobranchial cartilages as well as impaired ceratohyal, Meckel’s cartilage and ethmoid plate development. Moreover, mineralization of ceratohyal, Meckel’s cartilage, and vertebrae were downregulated during bone development. Taken together, we concluded that topiramate impaired oogenesis in the maternal reproductive system, and then caused offspring cartilage malformation or bone dysplasia.
Keywords: topiramate; ceratobranchial defect; teratology; zebrafish

摘要：托吡酯通常被用于儿童和成人的癫痫治疗。最近的临床数据表明，孕妇托吡酯的服用会增加胎儿唇腭裂的风险。为了更好的认知托吡酯潜在的影响，我们对成年雌性斑马鱼进行托吡酯给药来研究成年雌性斑马鱼及其后代的形态变化。结果表明托吡酯给药的雌鱼中，卵子成熟有所下降，并且在胚胎发生过程中后代存活率严重下降。此外，大约23%的后代在颅面区表现为的软骨畸形，比如角腮节软骨的缺失以及舌骨角、Meckel’s软骨和筛骨发育的缺陷。并且，舌骨角、Meckel’s软骨和脊椎的矿化作用在骨骼发育时有所下调。最后，我们的结论是在母体生殖系统中托吡酯使卵子发生受损，然后造成后代软骨畸形或者骨骼发育异常。

Epilepsy：癫痫  oral clefts：唇腭裂  dose：给药  morphologies：形态学  cartilage malformation:软骨畸形  craniofacial area：颅面区 ceratobranchial：角腮节  ceratohyal：舌骨角 ethmoid：筛骨  mineralization：矿化作用 vertebrae：脊椎  dysplasia：发育不良 发育异常

关键词：托吡酯  角腮节缺陷  畸形学 斑马鱼