title: 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 neurotoxicity in vitro. In particular, such tissue would be ideal for high-throughput screens that can be used to identify novel neurotoxic or neurotherapeutic compounds. We have previously established a high-throughput screening platform 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 neurotoxicity screens.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, United States. Electronic address: malikn@mail.nih.gov.
authors.forename: Nasir
authors.initials: N
authors.lastname: Malik
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, United States.
authors.forename: Anastasia G
authors.initials: AG
authors.lastname: Efthymiou
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Karly
authors.initials: K
authors.lastname: Mather
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Chester
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, United States.
authors.forename: Xiantao
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, United States; National Institute of Health Center for Regenerative Medicine, National Institutes of Health, United States.
authors.forename: Mahendra S
authors.initials: MS
authors.lastname: Rao
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D058953:Neural Stem Cells / Q000187:drug effects*; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*
keywords: Cardiac glycosides; Neural stem cells; Neurotoxicity screening