Journal
TOXICOLOGICAL SCIENCES
Volume 178, Issue 1, Pages 71-87Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfaa136
Keywords
alternatives to animal testing; human-induced pluripotent stem cell (hiPSC)-derived neuronal models; microelectrode array (MEA); rodent primary cortical cultures; seizure liability assessment
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Funding
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [50308-372160]
- Faculty of Veterinary Medicine (Utrecht University, The Netherlands)
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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 mu M), linopirdine (LOEC 1 mu M), and pilocarpine (LOEC 0.3 mu M). However, hiPSCderived cultures were about 3 times more sensitive for exposure to pentylenetetrazole (LOEC 30 mu M) than rodent primary cortical cultures (LOEC 100 mu M). Sensitivity of hiPSC-derived cultures for chlorpromazine, phenytoin, and enoxacin was 1030 times higher (LOECs 0.1, 0.3, and 0.1 mu M, respectively) than in rodent cultures (LOECs 10, 3, and 3 mu M, 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.
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