Compounds with species and cell type specific toxicity identified in a 2000 compound drug screen of neural stem cells and rat mixed cortical neurons

Abstract Human primary neural tissue is a vital component for the quick and simple determination of chemical compound neurotoxicityin vitro . In particular, such tissue would be ideal for high-throughput screensthat can be used to identify novel neurotoxicor neurotherapeutic compounds. We have previously established a high-throughput screeningplatform using human induced pluripotent stem cell(iPSC)-derived neural stem cells(NSCs) and neurons. In this study, we conducted a 2000 compound screen with human NSCs and rat cortical cells to identify compounds that are selectively toxic to each group. Approximately 100 of the tested compounds showed specific toxicity to human NSCs. A secondary screen of a small subset of compounds from the primary screen on human iPSCs, NSC-derived neurons, and fetal astrocytes validated the results from >80% of these compounds with some showing cell specific toxicity. Amongst those compounds were several cardiac glycosides, all of which were selectively toxic to the human cells. As the screen was able to reliably identify neurotoxicants, many with species and cell-type specificity, this study demonstrates the feasibility of this NSC-driven platform for higher-throughput neurotoxicityscreens.