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.

Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

“…These data suggest that the NeuroGlycoTest is able to detect specific effects on neurite glycosylation in the absence of general cytotoxicity and with higher sensitivity compared to neurite area measurements. This assay is therefore a useful novel addition to a battery of tests that are able to pick up alerts for potential neurotoxicants and modifiers of neural function (Bal-Price et al 2017;Gerhardt et al 2001;Hansson et al 2000;Hirt et al 2000;Ruszkiewicz et al 2018;Schultz et al 2015;Tiffany-Castiglioni et al 2006;Vassallo et al 2017;Zimmer et al 2011a, b). Based on the overall results of such a test battery, potential toxicants may be prioritized for further testing Li et al 2019;Schmidt et al 2017;Smirnova et al 2014;van Thriel et al 2012).…”

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

“…Combining brain tissue models with BBB models has been attempted in order to set up a general in vitro testing platform for neurotoxicity. Shultz et al generated their BBB model using bovine endothelial cells co-cultured with rat glial cells that separated the 'luminal compartment' from murine neuronal networks (a 2D model) or rat re-aggregating brain cell cultures (a 3D model) on the 'parenchymal' side in the well (Schultz et al 2015). This integrated testing system allowed analysis of whether the drug passed or damaged the BBB, as well as metabolomics, transcriptomics, proteomics, and functional (e.g.…”

“…The observed metabolomics changes also translated to changes in activity patterns, as measured by MEA. The MEA results provided 'fingerprints'" characteristic of the different classes of drugs, making MEA a promising early-predictive and sensitive tool for in vitro neurotoxicity testing (Schultz et al 2015).…”

Neuroprotective effect of total glycosides from paeonies against neurotoxicity induced by strychnos alkaloids related to recovering the levels of neurotransmitters and neuroendocrine hormones in rat serum and brain

“…The nervous system is one of the systems with high probability of adverse reactions caused by traditional Chinese medicines. [1][2][3] It has been widely reported that neurotoxicity is responsible for some neurodegenerative diseases and brain injuries. 4,5 It is very meaningful to nd a comprehensive and effective strategy to indicate herb-induced neurotoxicity.…”