Comparative study for the IMI2-NeuroDeRisk project on microelectrode arrays to derisk drug-induced seizure liability

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Jin Zhai , Martin Traebert , Kurt Zimmermann , Annie Delaunois , Leandro Royer , Giorgia Salvagiotto , Coby Carlson , Armando Lagrutta
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引用次数: 1

Abstract

Introduction

In the framework of the IMI2-NeuroDeRisk consortium, three in vitro electrophysiology assays were compared to improve preclinical prediction of seizure-inducing liabilities.

Methods

Two cell models, primary rat cortical neurons and human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with hiPSC-derived astrocytes were tested on two different microelectrode array (MEA) platforms, Maestro Pro (Axion Biosystems) and Multiwell-MEA-System (Multi Channel Systems), in three separate laboratories. Pentylenetetrazole (PTZ) and/or picrotoxin (PTX) were included in each plate as positive (n = 3–6 wells) and ≤0.2% DMSO was used as negative controls (n = 3–12 wells). In general, concentrations in a range of 0.1–30 μM were tested, anchored, when possible, on clinically relevant exposures (unbound Cmax) were tested. Activity thresholds for drug-induced changes were set at 20%. To evaluate sensitivity, specificity and predictivity of the cell models, seizurogenic responses were defined as changes in 4 or more endpoints. Concentration dependence trends were also considered.

Results

Neuronal activity of 33 compounds categorized as positive tool drugs, seizure-positive or seizure-negative compounds was evaluated. Acute drug effects (<60 min) were compared to baseline recordings. Time points < 15 min exhibited stronger, less variable responses to many of the test agents. For many compounds a reduction and cessation of neuronal activity was detected at higher test concentrations. There was not a single pattern of seizurogenic activity detected, even among tool compounds, likely due to different mechanisms of actions and/or off-target profiles. A post-hoc analysis focusing on changes indicative of neuronal excitation is presented.

Conclusion

All cell models showed good sensitivity, ranging from 70 to 86%. Specificity ranged from 40 to 70%. Compared to more conventional measurements of evoked activity in hippocampal slices, these plate-based models provide higher throughput and the potential to study subacute responses. Yet, they may be limited by the random, spontaneous nature of their network activity.

IMI2-NeuroDeRisk项目关于微电极阵列降低药物诱发癫痫发作风险的比较研究。
在IMI2-NeuroDeRisk联盟的框架下,比较了三种体外电生理试验,以改善癫痫诱发责任的临床前预测。方法:在3个独立实验室的Maestro Pro (Axion Biosystems)和Multiwell-MEA-System (Multi Channel Systems)两种不同的微电极阵列(MEA)平台上,对原代大鼠皮质神经元和人诱导多能干细胞(hiPSC)衍生的谷氨酸能神经元与hiPSC衍生的星形胶质细胞共培养的两种细胞模型进行测试。以戊四唑(PTZ)和(或)微毒素(PTX)为阳性(n = 3-6孔),以≤0.2% DMSO为阴性(n = 3-12孔)。通常,测试0.1-30 μM范围内的浓度,并尽可能锚定在临床相关暴露(未结合Cmax)上进行测试。药物引起的变化的活性阈值设定为20%。为了评估细胞模型的敏感性、特异性和预测性,癫痫尿源性反应被定义为4个或更多终点的变化。浓度依赖趋势也被考虑。结果:测定了33种工具药物阳性、癫痫阳性和癫痫阴性化合物的神经元活性。结论:所有细胞模型均具有良好的敏感性,敏感性范围为70 ~ 86%。特异性从40%到70%不等。与传统的海马切片诱发活动测量方法相比,这些基于平板的模型提供了更高的通量和研究亚急性反应的潜力。然而,它们可能受到网络活动随机性和自发性的限制。
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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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