Post-Traumatic Epilepsy in Zebrafish Is Drug-Resistant and Impairs Cognitive Function
Post-Traumatic Epilepsy in Zebrafish Is Drug-Resistant and Impairs Cognitive Function
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DOI：
10.1089/neu.2021.0156
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发表时间：
2021-09-27
影响因子：
4.2
通讯作者：
Reid, Aylin Y.
中科院分区：
文献类型：
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作者：
Cho, Sung-Joon;Park, Eugene;Reid, Aylin Y.
创伤后癫痫(PTE)是创伤性脑损伤(TBI)后获得性癫痫。尽管有20多种抗癫痫药物(ASM)可用，但目前还没有办法阻止脑外伤幸存者的癫痫发生，许多PTE病例产生了耐药性。重要的是，ASM的不良影响会显著影响患者的生活质量。哺乳动物模型是研究难治性PTE的常用模型，但价格昂贵且费时费力。斑马鱼模型已经成为研究癫痫的流行模型，但大多数都集中在幼虫身上，到目前为止还没有关于获得性癫痫的成年斑马鱼模型的药理筛选的报道。有效的动物模型对于理解PTE和开发新的治疗方法至关重要。本研究的目的是描述导致PTE发展的斑马鱼脑外伤模型的认知障碍。使用行为和电生理相结合的方法，我们还表征了最常用的管理PTE的ASM(丙戊酸盐、卡马西平和苯妥英)的药理作用。患有PTE的斑马鱼表现出学习和记忆障碍，决策困难，社会偏好降低。丙戊酸盐和卡马西平对行为发作的保护作用有限，这三种药物都未能显著减少脑电发作。在斑马鱼中观察到的TBI和ASM的负面影响与在其他动物中观察到的一样，使PTE的斑马鱼模型成为研究难治性和耐药癫痫的高通量模型。
Post-traumatic epilepsy (PTE) is acquired epilepsy after traumatic brain injury (TBI). Despite the availability of more than 20 antiseizure medications (ASMs), there is no way at present to prevent epileptogenesis in TBI survivors, and many cases of PTE become drug-resistant. Importantly, the adverse effects of ASMs can significantly affect patients' quality of life. Mammalian models are commonly used for studying refractory PTE, but are expensive and laborious. Zebrafish models have become popular for studying epilepsy, but most focus on larvae, and there have been no reports to date of pharmacological screening in an adult zebrafish model of acquired epilepsy. Valid animal models are critical for understanding PTE and for developing novel therapeutics. The aim of the present study was to characterize the cognitive impairments of a zebrafish model of TBI that leads to the development of PTE. Using combined behavioral and electrophysiological approaches, we also characterized the pharmacological effects of the most commonly used ASMs to manage PTE (valproate, carbamazepine, and phenytoin). Zebrafish with PTE exhibited impairments in learning and memory, difficulty in decision making, and reduced social preference. Valproate and carbamazepine had a limited protective effect against behavioral seizures, and all three drugs failed to significantly reduce electrographical seizures. The negative impacts of TBI and ASMs in zebrafish parallel those observed in other animals, making the zebrafish model of PTE a promising high-throughput model of refractory and drug-resistant epilepsy.