Article ; Online: Comparative study for the IMI2-NeuroDeRisk project on microelectrode arrays to derisk drug-induced seizure liability.
Journal of pharmacological and toxicological methods
2023 Volume 123, Page(s) 107297
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 ... ...
| 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 C 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. |
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| MeSH term(s) | Rats ; Humans ; Animals ; Microelectrodes ; Cells, Cultured ; Induced Pluripotent Stem Cells ; Seizures/chemically induced ; Neurons |
| Language | English |
| Publishing date | 2023-07-25 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1105919-9 |
| ISSN | 1873-488X ; 1056-8719 |
| ISSN (online) | 1873-488X |
| ISSN | 1056-8719 |
| DOI | 10.1016/j.vascn.2023.107297 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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