Drug-induced neurotoxicity is a critical safety concern in central nervous system (CNS) drug development, often contributing to high attrition rates and post-market adverse event reports. Conventional in vitro models typically lack the cellular diversity and functional complexity of the human brain, limiting their predictive value. Similarly, animal models may not reliably replicate human-specific neurotoxic responses due to interspecies differences.

To overcome these limitations, Wang et al. (2022) utilized AxoSim’s three-dimensional (3D) human neural spheroid model derived from induced pluripotent stem cells (iPSCs). This model co-cultures cortical neurons and astrocytes in a 3D architecture that mimics aspects of human brain structure and function. The system supports spontaneous calcium oscillations and expresses key lineage markers, enabling assessment of both structural and functional responses to chemical exposure.

‍

Key Highlights

‍

• Physiologically Relevant and Functional: The 3D neural spheroid model recapitulates human cortical architecture, displaying spontaneous calcium oscillations and expressing neuronal and glial markers.
  ‍
• Robust Detection of Neurotoxicity: The model identified functional and morphological disruptions caused by diverse neurotoxicants—including chemotherapeutics, antidepressants, and antipsychotics—using calcium imaging and high-content analysis.
  ‍
• High Predictive Accuracy: With an ROC AUC of 0.91, the model showed strong ability to discriminate neurotoxic compounds, supporting its use in early-stage CNS drug safety screening.

‍

This application note summarizes key findings from the study and highlights how the model enables robust, multiparametric detection of neurotoxic effects, using a panel of diverse pharmaceutical and environmental compounds.