{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:17:53Z","timestamp":1791332273983,"version":"4.3.1"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Janssen Pharmaceutica NV"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Drug-induced seizure liability is a significant safety issue and the basis for attrition in drug development. Occurrence in late development results in increased costs, human risk, and delayed market availability of novel therapeutics. Therefore, there is an urgent need for biologically relevant, in vitro high-throughput screening assays (HTS) to predict potential risks for drug-induced seizure early in drug discovery. We investigated drug-induced changes in neural Ca2+ oscillations, using fluorescent dyes as a potential indicator of seizure risk, in hiPSC-derived neurons co-cultured with human primary astrocytes in both 2D and 3D forms. The dynamics of synchronized neuronal calcium oscillations were measured with an FDSS kinetics reader. Drug responses in synchronized Ca2+ oscillations were recorded in both 2D and 3D hiPSC-derived neuron\/primary astrocyte co-cultures using positive controls (4-aminopyridine and kainic acid) and negative control (acetaminophen). Subsequently, blinded tests were carried out for 25 drugs with known clinical seizure incidence. Positive predictive value (accuracy) based on significant changes in the peak number of Ca2+ oscillations among 25 reference drugs was 91% in 2D vs. 45% in 3D hiPSC-neuron\/primary astrocyte co-cultures. These data suggest that drugs that alter neuronal activity and may have potential risk for seizures can be identified with high accuracy using an HTS approach using the measurements of Ca2+ oscillations in hiPSC-derived neurons co-cultured with primary astrocytes in 2D.<\/jats:p>","DOI":"10.3390\/cells12060958","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:46:43Z","timestamp":1679471203000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["High-Throughput Screening Assay for Detecting Drug-Induced Changes in Synchronized Neuronal Oscillations and Potential Seizure Risk Based on Ca2+ Fluorescence Measurements in Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neuronal 2D and 3D Cultures"],"prefix":"10.3390","volume":"12","author":[{"given":"Hua-Rong","family":"Lu","sequence":"first","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Seo","sequence":"additional","affiliation":[{"name":"Elixirgen Scientific, Incorporated, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9159-9554","authenticated-orcid":false,"given":"Mohamed","family":"Kreir","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0406-0217","authenticated-orcid":false,"given":"Tetsuya","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Elixirgen Scientific, Incorporated, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Yamoto","sequence":"additional","affiliation":[{"name":"Healthcare Business Group, Drug Discovery Business Department, Ricoh Company Ltd., Tokyo 143-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Altrocchi","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"van Ammel","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fetene","family":"Tekle","sequence":"additional","affiliation":[{"name":"Statistics and Decision Sciences, Global Development, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ly","family":"Pham","sequence":"additional","affiliation":[{"name":"Computational Biology & Toxicology, Preclinical Sciences and Translational Safety, A Division of Janssen Pharmaceutica NV, San Diego, CA 921921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yao","sequence":"additional","affiliation":[{"name":"Computational Biology & Toxicology, Preclinical Sciences and Translational Safety, A Division of Janssen Pharmaceutica NV, San Diego, CA 921921, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ard","family":"Teisman","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Gallacher","sequence":"additional","affiliation":[{"name":"Global Safety Pharmacology, Preclinical Sciences and Translational Safety, Janssen R&D, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.vascn.2016.06.001","article-title":"Safety pharmacology investigations on the nervous system: An industry survey","volume":"81","author":"Authier","year":"2016","journal-title":"J. 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