In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells
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 significan...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2018.00590/full |
| _version_ | 1818528976946069504 |
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| author | Alastair I. Grainger Marianne C. King David A. Nagel H. Rheinallt Parri Michael D. Coleman Eric J. Hill |
| author_facet | Alastair I. Grainger Marianne C. King David A. Nagel H. Rheinallt Parri Michael D. Coleman Eric J. Hill |
| author_sort | Alastair I. Grainger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T06:57:06Z |
| format | Article |
| id | doaj.art-3d308861edbf4efeb4f5125aca345178 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-11T06:57:06Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-3d308861edbf4efeb4f5125aca3451782022-12-22T01:16:44ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2018-08-011210.3389/fnins.2018.00590396025In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem CellsAlastair I. GraingerMarianne C. KingDavid A. NagelH. Rheinallt ParriMichael D. ColemanEric J. HillThe 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.https://www.frontiersin.org/article/10.3389/fnins.2018.00590/fulliPSC neuronsastrocytesseizuresin vitrosafety pharmacology |
| spellingShingle | Alastair I. Grainger Marianne C. King David A. Nagel H. Rheinallt Parri Michael D. Coleman Eric J. Hill In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells Frontiers in Neuroscience iPSC neurons astrocytes seizures in vitro safety pharmacology |
| title | In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells |
| title_full | In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells |
| title_fullStr | In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells |
| title_full_unstemmed | In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells |
| title_short | In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells |
| title_sort | in vitro models for seizure liability testing using induced pluripotent stem cells |
| topic | iPSC neurons astrocytes seizures in vitro safety pharmacology |
| url | https://www.frontiersin.org/article/10.3389/fnins.2018.00590/full |
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