In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells.
In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells.
复制标题
使用诱导多能干细胞进行癫痫发作责任测试的体外模型。
DOI：
10.3389/fnins.2018.00590
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发表时间：
2018
影响因子：
4.3
通讯作者：
Hill EJ
中科院分区：
文献类型：
--
作者：
Grainger AI;King MC;Nagel DA;Parri HR;Coleman MD;Hill EJ
大脑是身体中最复杂的器官，控制着我们的最高功能，并调节着包含整个生理系统的无数过程。前瞻性治疗实体对脑和中枢神经系统（CNS）的影响可能会导致显著损伤，因此，CNS毒性试验构成安全性药理学研究“核心组合”的一部分。药物诱导的癫痫发作是药物开发过程中化合物消耗的主要原因。目前，大鼠离体海马切片测定是致龋性研究的标准选择，其次是原代啮齿动物培养。这些模型可以响应不同的代理和预测癫痫发作的结果，但这些动物为基础的方法的相关性，有效性和成本的争议，导致了在开发人源性模型的兴趣。现有平台往往利用啮齿动物，因此缺乏人类受体和其他药物靶点，这可能产生误导性数据，难以进行物种间外推。目前的电生理学方法通常用于低通量容量，并且可能忽略网络功能。人源性诱导多能干细胞（iPSC）是神经毒性测试的一种有前途的途径，越来越多地用于药物筛选和疾病建模。此外，iPSC衍生模型与功能技术（如多电极阵列（MEA）分析）的组合可以提供有关神经元网络功能的信息，对破坏不同途径的神经毒性作用的敏感性增加。使用体外人iPSC衍生的神经模型进行神经毒性研究，结合高通量技术（如MEA记录），可能是对现有临床前毒性试验策略的适当补充。
The brain is the most complex organ in the body, controlling our highest functions, as well as regulating myriad processes which incorporate the entire physiological system. The effects of prospective therapeutic entities on the brain and central nervous system (CNS) may potentially cause significant injury, hence, CNS toxicity testing forms part of the “core battery” of safety pharmacology studies. Drug-induced seizure is a major reason for compound attrition during drug development. Currently, the rat ex vivo hippocampal slice assay is the standard option for seizure-liability studies, followed by primary rodent cultures. These models can respond to diverse agents and predict seizure outcome, yet controversy over the relevance, efficacy, and cost of these animal-based methods has led to interest in the development of human-derived models. Existing platforms often utilize rodents, and so lack human receptors and other drug targets, which may produce misleading data, with difficulties in inter-species extrapolation. Current electrophysiological approaches are typically used in a low-throughput capacity and network function may be overlooked. Human-derived induced pluripotent stem cells (iPSCs) are a promising avenue for neurotoxicity testing, increasingly utilized in drug screening and disease modeling. Furthermore, the combination of iPSC-derived models with functional techniques such as multi-electrode array (MEA) analysis can provide information on neuronal network function, with increased sensitivity to neurotoxic effects which disrupt different pathways. The use of an in vitro human iPSC-derived neural model for neurotoxicity studies, combined with high-throughput techniques such as MEA recordings, could be a suitable addition to existing pre-clinical seizure-liability testing strategies.
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影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre
DOI：
10.1016/b978-012088554-1/50005-0
发表时间：
2006-01-01
期刊：
MODELS OF SEIZURES AND EPILEPSY
影响因子：
--
作者：
Dichter, Marc A.;Pollard, John
通讯作者：
Pollard, John
影响因子：
16.2
作者：
Grienberger, Christine;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
1.2
作者：
Frega, Monica;van Gestel, Sebastianus H. C.;Kasri, Nael Nadif
通讯作者：
Kasri, Nael Nadif
影响因子：
46.9
作者：
Chambers, Stuart M.;Fasano, Christopher A.;Papapetrou, Eirini P.;Tomishima, Mark;Sadelain, Michel;Studer, Lorenz
通讯作者：
Studer, Lorenz