Repository: Freie Universität Berlin, Math Department

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

Schultz, L. and Zurich, M.-G. and Culot, M. and da Costa, A. and Landry, C. and Bellwon, P. and Kristl, T. and Hörmann, K. and Ruzek, S. and Aiche, S. and Reinert, K. and Bielow, C. and Gosselet, F. and Cecchelli, R. and Huber, C. G. and Schroeder, O. H.-U. and Gramowski-Voss, A. and Weiss, D. G. and Bal-Price, A. (2015) Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. Toxicology in Vitro, 30 (1). pp. 138-165. ISSN 08872333

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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. Abbreviations: BBB, blood brain barrier; DMSO, dimethylsulfoxide; EC, endothelial cells; DIV, day in vitro; IPA, Ingenuity Pathway Analysis; ITS, integrated testing strategy; LY, Lucifer Yellow; MEA, micro-electrode array; RH, Ringer HEPES medium; SPSS, Statistical Package for the Social Sciences

Item Type:Article
Additional Information:Online publication: May 2015
Uncontrolled Keywords:In vitro blood brain barrier; MEA; Neuronal network culture; OMICs; Drug development; 3D brain culture
Subjects:Mathematical and Computer Sciences > Computer Science
Divisions:Department of Mathematics and Computer Science > Institute of Computer Science > Algorithmic Bioinformatics Group
ID Code:1736
Deposited By: Anja Kasseckert
Deposited On:01 Oct 2015 08:35
Last Modified:15 Nov 2016 13:58

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