title: Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models.
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.
authors.affiliation: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, D-18051 Rostock, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Schultz
authors.affiliation: Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Zurich
authors.affiliation: Laboratoire de la barrière hémato-encéphalique (LBHE) - EA2465, Université d'Artois, Faculté Jean Perrin, 62307 Lens, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Culot
authors.affiliation: Laboratoire de la barrière hémato-encéphalique (LBHE) - EA2465, Université d'Artois, Faculté Jean Perrin, 62307 Lens, France.
authors.forename: Anaelle
authors.initials: A
authors.lastname: da Costa
authors.affiliation: Laboratoire de la barrière hémato-encéphalique (LBHE) - EA2465, Université d'Artois, Faculté Jean Perrin, 62307 Lens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Landry
authors.affiliation: Department of Toxicology, University of Wuerzburg, D-97078 Wuerzburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bellwon
authors.affiliation: Department of Molecular Biology, Paris-Lodron University, Salzburg, Austria.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kristl
authors.affiliation: Department of Molecular Biology, Paris-Lodron University, Salzburg, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hörmann
authors.affiliation: Department of Molecular Biology, Paris-Lodron University, Salzburg, Austria.
authors.forename: Silke
authors.initials: S
authors.lastname: Ruzek
authors.affiliation: Department of Mathematics and Computer Science, Freie Universitaet Berlin, D-14195 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Aiche
authors.affiliation: Department of Mathematics and Computer Science, Freie Universitaet Berlin, D-14195 Berlin, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Reinert
authors.affiliation: Department of Mathematics and Computer Science, Freie Universitaet Berlin, D-14195 Berlin, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Bielow
authors.affiliation: Laboratoire de la barrière hémato-encéphalique (LBHE) - EA2465, Université d'Artois, Faculté Jean Perrin, 62307 Lens, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Gosselet
authors.affiliation: Laboratoire de la barrière hémato-encéphalique (LBHE) - EA2465, Université d'Artois, Faculté Jean Perrin, 62307 Lens, France.
authors.forename: Romeo
authors.initials: R
authors.lastname: Cecchelli
authors.affiliation: Department of Molecular Biology, Paris-Lodron University, Salzburg, Austria.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Huber
authors.affiliation: NeuroProof GmbH, D-18119 Rostock, Germany.
authors.forename: Olaf H-U
authors.initials: OH
authors.lastname: Schroeder
authors.affiliation: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, D-18051 Rostock, Germany; NeuroProof GmbH, D-18119 Rostock, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gramowski-Voss
authors.affiliation: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, D-18051 Rostock, Germany; NeuroProof GmbH, D-18119 Rostock, Germany.
authors.forename: Dieter G
authors.initials: DG
authors.lastname: Weiss
authors.affiliation: European Commission Joint Research Centre, Institute for Health and Consumer Protection, I-21027 Ispra, VA, Italy. Electronic address: anna.price@jrc.ec.europa.eu.
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D055432:Metabolomics; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D020258:Neurotoxicity Syndromes / Q000175:diagnosis; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D040901:Proteomics; D051381:Rats
chemical_list: D009498:Neurotoxins
keywords: 3D brain culture; Drug development; In vitro blood brain barrier; MEA; Neuronal network culture; OMICs