Shin Jun-Nyeong, Lee Ki-Baek, Butterworth Woojae, Park Soo-Kyung, Kim Jung-Yeon, Kim Sohee
Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Zefit Inc, Daegu, South Korea.
Front Pharmacol. 2022 Dec 8;13:1055424. doi: 10.3389/fphar.2022.1055424. eCollection 2022.
Pharmacological evaluation of antiepileptic drugs (AEDs) using mammalian animals takes long time and is expensive. The zebrafish is a species commonly used to study brain functions, neurological diseases, and drug toxicity, and attracts more attention as an alternative animal model to substitute or supplement mammalian animals in drug development. Electroencephalogram (EEG) is a key indicator for diagnosing brain diseases such as epilepsy, by directly measuring the brain activity. We propose a novel method for pharmacological evaluation of AEDs based on EEG from adult zebrafish, which allows researchers to select more clinically valuable drugs at the early stage of AED screening. To evaluate the efficacy of AEDs, zebrafish EEG signals were measured after administering six AEDs (valproate acid, gabapentin, ethosuximide, oxcarbazepine, tiagabine, and topiramate) at various doses to pentylenetetrazol (PTZ)-induced seizure models. The change in seizure activity was investigated according to doses. The antiepileptic effect was determined by observing a significant decrease in at least one out of three indicators of the number, total duration, and mean duration of ictal events. Using EEG signals from adult zebrafish, antiepileptic effects were observed with all six AEDs. Among them, antiepileptic effects depending on dose were confirmed with valproate acid, gabapentin, ethosuximide, and tiagabine. Moreover, the 50% effective doses (ED50) of valproate acid and tiagabine were determined based on zebrafish EEG for the first time, indicating that the quantitative inter-species comparison of the AED efficacy is possible between zebrafish and mammals such as rodents. The results show that zebrafish can be used to effectively and quantitatively evaluate the efficacy of AEDs based on EEG, the same method to evaluate antiepileptic effects in mammals, suggesting that the proposed method can contribute in reducing the cost and duration of search for AEDs and thus accelerate the drug development cycles.
使用哺乳动物进行抗癫痫药物（AEDs）的药理评估耗时且昂贵。斑马鱼是一种常用于研究脑功能、神经疾病和药物毒性的物种，作为替代或补充哺乳动物用于药物开发的动物模型，它正吸引着更多关注。脑电图（EEG）是通过直接测量大脑活动来诊断癫痫等脑部疾病的关键指标。我们提出了一种基于成年斑马鱼脑电图对AEDs进行药理评估的新方法，该方法能让研究人员在AEDs筛选的早期阶段选择更具临床价值的药物。为了评估AEDs的疗效，在戊四氮（PTZ）诱导的癫痫模型中，以不同剂量给予六种AEDs（丙戊酸、加巴喷丁、乙琥胺、奥卡西平、噻加宾和托吡酯）后，测量斑马鱼的EEG信号。根据剂量研究癫痫活动的变化。通过观察发作事件的数量、总持续时间和平均持续时间这三个指标中至少一个的显著下降来确定抗癫痫效果。使用成年斑马鱼的EEG信号，观察到所有六种AEDs都有抗癫痫作用。其中，丙戊酸、加巴喷丁、乙琥胺和噻加宾的抗癫痫作用与剂量有关。此外，首次基于斑马鱼脑电图确定了丙戊酸和噻加宾的50%有效剂量（ED50），这表明在斑马鱼和啮齿类等哺乳动物之间进行AEDs疗效的定量种间比较是可能的。结果表明，斑马鱼可用于基于脑电图有效且定量地评估AEDs的疗效，这与在哺乳动物中评估抗癫痫效果的方法相同，表明所提出的方法有助于降低AEDs研发的成本和时间，并因此加速药物开发周期。
