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Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models

Luise Schultz 1 Marie-Gabrielle Zurich 2 Maxime Culot 3 Anaelle da Costa 3 Christophe Landry 3 Patricia Bellwon 4 Theresa Kristl 5 Katrin Hörmann 5 Silke Ruzek 5 Stephan Aiche 6 Knut Reinert 7 Chris Bielow 6 Fabien Gosselet 3 Roméo Cecchelli 3 Christian Huber 8 Olaf H.-U. Schroeder Alexandra Gramowski-Voss 9 Dieter Weiss 9 Anna Bal-Price 10
1 University of Rostock
2 UNIL - Université de Lausanne
3 LBHE - Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique
4 University of Würzburg = Universität Würzburg
5 PLUS - Paris-Lodron-Universität Salzburg
6 Freie Universität Berlin
7 Freie Universität Berlin - Department of Mathematics and Computer Science
8 Universität Salzburg
9 Universität Rostock
10 Institute for Health and Consumer Protection
Abstract : The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.
Keywords : OMICs Neuronal network culture MEA 3D brain culture Drug development In vitro blood brain barrier
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https://hal-univ-artois.archives-ouvertes.fr/hal-02513335
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Submitted on : Friday, January 14, 2022 - 4:43:00 PM
Last modification on : Wednesday, January 26, 2022 - 1:13:40 PM

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Luise Schultz, Marie-Gabrielle Zurich, Maxime Culot, Anaelle da Costa, Christophe Landry, et al.. Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. Toxicology in Vitro, Elsevier, 2015, 30 (1), pp.138-165. ⟨10.1016/j.tiv.2015.05.016⟩. ⟨hal-02513335⟩

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