Title: Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in the complementary CNS in vitro models
Authors: SCHULTZ LuiseZURICH Marie-GabrielleCULOT MaximeFABULAS DA COSTA AnaelleLANDRY ChristopheBELLWON PatriciaKRISTL TheresaHÖRMANN KatrinRUZEK SilkeAICHE StefanREINERT KnutBIELOW ChrisGOSSELET FabienCECCHELLI RomeoHUBER ChristianSCHROEDER Olaf H.-U.GRAMOWSKI-VOSS AlexandraWEISS Dieter G.PRICE Anna
Citation: TOXICOLOGY IN VITRO vol. 30 no. 1, Part A p. 138-165
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Publication Year: 2015
JRC N°: JRC91298
ISSN: 0887-2333
URI: http://www.sciencedirect.com/science/article/pii/S0887233315001204
http://publications.jrc.ec.europa.eu/repository/handle/JRC91298
DOI: 10.1016/j.tiv.2015.05.016
Type: Articles in periodicals and books
Abstract: The present study was performed in an attempt to develop an in vitro integrated testing strategy to evaluate neurotoxicity of drugs during development phase. A number of endpoints was analyzed using two complementary brain cell culture models, and an in vitro blood-brain barrier model after acute, sub-chronic, and repeated-dose treatments with a series of selected drugs. The developed in vitro BBB model allowed to detect toxic effects on the BBB and to evaluate drug transport through the BBB for prediction free brain concentrations of studied drugs. The electrical activity of cortical neuronal networks recorded with a micro-electrode array was found to be a good tool to predict the neuroactivity and neurotoxicity of drugs and it is suggested as a first-step high content screening test. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found well suitable for OMICs analyzes. The obtained data suggest that an in vitro integrated testing strategy (ITS), including toxicity to and transport through BBB, as well as metabolomics, proteomics and neuronal electrical activity, measured in stable rodent brain cell culture systems (in the future human stem cell-derived neuronal models), may considerably improve current drug-induced neurotoxicity evaluation. Robustness of this ITS has to be further evaluated with a larger number of studied drugs.
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