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INTRODUCTION

One-third of people with epilepsy continue to experience seizures despite treatment with existing anti-seizure medications (ASMs). The failure of modern ASMs to substantially improve epilepsy prognosis has been partly attributed to overreliance on acute rodent models in preclinical drug development as they do not adequately recapitulate the mechanisms of human epilepsy, are labor-intensive and unsuitable for high-throughput screening (HTS). There is an urgent need to find human-relevant HTS models in preclinical drug development to identify novel anti-seizure compounds.

OBJECTIVES

This paper developed high-throughput preclinical screening models to identify new ASMs.

METHODS

14 natural compounds (α-asarone, curcumin, vinpocetine, magnolol, ligustrazine, osthole, tanshinone IIA, piperine, gastrodin, quercetin, berberine, chrysin, schizandrin A and resveratrol) were assessed for their ability to suppress epileptiform activity as measured by multi-electrode arrays (MEA) in neural cultures derived from human induced pluripotent stem cells (iPSCs). In parallel, they were tested for anti-seizure effects in zebrafish and mouse models, which have been widely used in development of modern ASMs. The effects of the compounds in these models were compared. Two approved ASMs were used as positive controls.

RESULTS

Epileptiform activity could be induced in iPSCs-derived neurons following treatment with 4-aminopyridine (4-AP) and inhibited by standard ASMs, carbamazepine, and phenytoin. Eight of the 14 natural compounds significantly inhibited the epileptiform activity in iPSCs-derived neurons. Among them, piperine, magnolol, α-asarone, and osthole showed significant anti-seizure effects both in zebrafish and mice. Comparative analysis showed that compounds ineffective in the iPSCs-derived neural model also showed no anti-seizure effects in the zebrafish or mouse models.

CONCLUSION

Our findings support the use of iPSCs-derived human neurons for first-line high-throughput screening to identify compounds with anti-seizure properties and exclude ineffective compounds. Effective compounds may then be selected for animal evaluation before clinical testing. This integrated approach may improve the efficiency of developing novel ASMs.

INTRODUCTION

OBJECTIVES

This paper developed high-throughput preclinical screening models to identify new ASMs.

METHODS

RESULTS

CONCLUSION

简介

尽管现有抗癫痫药物（ASM）治疗，仍有三分之一的癫痫患者持续发作。现代 ASM 在改善癫痫预后方面的失败部分归因于在临床前药物开发中过度依赖急性啮齿动物模型，因为它们不能充分再现人类癫痫的机制，而且劳动强度大，不适合高通量筛选（HTS）。迫切需要在临床前药物开发中找到与人类相关的 HTS 模型，以确定新型抗癫痫化合物。

目的

本文开发了高通量临床前筛选模型，以鉴定新型 ASM。

方法

评估了 14 种天然化合物（α-细辛脑、姜黄素、长春西汀、厚朴酚、川芎嗪、蛇床子素、丹参酮 IIA、胡椒碱、天麻素、槲皮素、小檗碱、白杨素、五味子 A 和白藜芦醇）抑制多电极阵列（MEA）测量的源自人诱导多能干细胞（iPSC）的神经培养物中癫痫样活动的能力。同时，在斑马鱼和小鼠模型中测试了它们的抗癫痫作用，这两种模型在现代 ASM 的开发中被广泛应用。比较了这些模型中化合物的作用。两种已批准的 ASM 被用作阳性对照。

结果

用 4-氨基吡啶（4-AP）处理后，iPSC 衍生神经元可诱导癫痫样活动，并被标准 ASM、卡马西平、苯妥英抑制。14 种天然化合物中有 8 种显著抑制了 iPSC 衍生神经元的癫痫样活动。其中，胡椒碱、厚朴酚、α-细辛脑和蛇床子素在斑马鱼和小鼠中均表现出显著的抗癫痫作用。比较分析表明，在 iPSC 衍生神经模型中无效的化合物在斑马鱼或小鼠模型中也没有抗癫痫作用。