Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in the complementary CNS in vitro models
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.
SCHULTZ Luise;
ZURICH Marie-Gabrielle;
CULOT Maxime;
FABULAS DA COSTA Anaelle;
LANDRY Christophe;
BELLWON Patricia;
KRISTL Theresa;
HÖRMANN Katrin;
RUZEK Silke;
AICHE Stefan;
REINERT Knut;
BIELOW Chris;
GOSSELET Fabien;
CECCHELLI Romeo;
HUBER Christian;
SCHROEDER Olaf H.U.;
GRAMOWSKI-VOSS Alexandra;
WEISS Dieter G.;
PRICE Anna;
2015-12-09
PERGAMON-ELSEVIER SCIENCE LTD
JRC91298
0887-2333,
http://www.sciencedirect.com/science/article/pii/S0887233315001204,
https://publications.jrc.ec.europa.eu/repository/handle/JRC91298,
10.1016/j.tiv.2015.05.016,
Additional supporting files
| File name | Description | File type | |
|---|
