Objective

Many safety failures occurring during the clinical trials on drugs are linked to central nervous system (CNS) toxicity. Peripheral neurotoxicity is also clinically relevant because it is frequent following chemotherapy, but peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. Therefore, relevant and predictive models are needed to detect the potential neurotoxicity of drug candidates, as early as possible during the drug discovery process.

Compared to in vivo systems, in vitro models are well suited to the study of biological processes in a more isolated context. They can help to elucidate underlying mechanisms of toxicity, identify the target cells of neurotoxicity and describe the cellular changes induced by neurotoxicants. However, to be relevant and predictive, the chosen cellular model(s) should recapitulate the in vivo situation and exhibit a proper neuronal phenotype.

In this study, we aimed at comparing two models in the frame of neurotoxicity assessment in vitro: differentiated SH-SY5Y cell line and induced pluripotent stem cell (iPSC)-derived neuronal cultures. SH-SY5Y cell line is widely used as a surrogate for neuronal cells, but it was originally derived from a metastatic neuroblastoma tumor. Two different iPSC-derived cultures were tested: CNS.4U™ and PERI.4U™ cells from Ncardia (Köln, Germany):  CNS4U™ cultures are a mix of iPSC-derived neurons and astrocytes, while PERI4U™ cultures are iPSC-derived peripheral neurons.

Cultures were exposed for 48 hours to increasing concentrations of 32 compounds from our in-house neurotoxicity library, and fixed cells were stained and imaged using our automated confocal microscopes (Molecular Devices). Cell numbers and neurite outgrowth length were analyzed to assess potential neurotoxic effects. The results indicate that CNS4U™ and PERI4U™ seem to be interesting and valuable alternatives to neuronal cell lines like SH-SY5Y for neurotoxicity assessment.