Applicability of hiPSC-Derived Neuronal Cocultures and Rodent Primary Cortical Cultures for In Vitro Seizure Liability Assessment
| Autor: | Tukker, Anke M, Wijnolts, Fiona M J, de Groot, Aart, Westerink, Remco H S, dIRAS RA-1, IRAS OH Toxicology |
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| Přispěvatelé: | dIRAS RA-1, IRAS OH Toxicology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Phenytoin AcademicSubjects/SCI01040 seizure liability assessment Induced Pluripotent Stem Cells Alternatives to animal testing Rodentia Pharmacology Toxicology Linopirdine 03 medical and health sciences alternatives to animal testing 0302 clinical medicine Seizures rodent primary cortical cultures Emerging Technologies Methods and Models Enoxacin medicine Animals Humans Chlorpromazine Cells Cultured Neurons AcademicSubjects/MED00305 Chemistry Amoxapine In vitro Coculture Techniques Featured 030104 developmental biology Pilocarpine microelectrode array (MEA) human-induced pluripotent stem cell (hiPSC)-derived neuronal models 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Toxicological Sciences, 178(1), 71. Oxford University Press Toxicological Sciences |
| ISSN: | 1096-6080 |
| Popis: | Seizures are life-threatening adverse drug reactions which are investigated late in drug development using rodent models. Consequently, if seizures are detected, a lot of time, money and animals have been used. Thus, there is a need for in vitro screening models using human cells to circumvent interspecies translation. We assessed the suitability of cocultures of human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes compared with rodent primary cortical cultures for in vitro seizure liability assessment using microelectrode arrays. hiPSC-derived and rodent primary cortical neuronal cocultures were exposed to 9 known (non)seizurogenic compounds (pentylenetetrazole, amoxapine, enoxacin, amoxicillin, linopirdine, pilocarpine, chlorpromazine, phenytoin, and acetaminophen) to assess effects on neuronal network activity using microelectrode array recordings. All compounds affect activity in hiPSC-derived cocultures. In rodent primary cultures all compounds, except amoxicillin changed activity. Changes in activity patterns for both cell models differ for different classes of compounds. Both models had a comparable sensitivity for exposure to amoxapine (lowest observed effect concentration [LOEC] 0.03 µM), linopirdine (LOEC 1 µM), and pilocarpine (LOEC 0.3 µM). However, hiPSC-derived cultures were about 3 times more sensitive for exposure to pentylenetetrazole (LOEC 30 µM) than rodent primary cortical cultures (LOEC 100 µM). Sensitivity of hiPSC-derived cultures for chlorpromazine, phenytoin, and enoxacin was 10-30 times higher (LOECs 0.1, 0.3, and 0.1 µM, respectively) than in rodent cultures (LOECs 10, 3, and 3 µM, respectively). Our data indicate that hiPSC-derived neuronal cocultures may outperform rodent primary cortical cultures with respect to detecting seizures, thereby paving the way towards animal-free seizure assessment. |
| Databáze: | OpenAIRE |
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