Toxicological Assessment of Drugs Based on Electrical Activities of Human iPSC-Derived Cortical Neurons, Sensory Neurons and Cerebral Organoids

Using human neurons derived from induced pluripotent stem cells (iPSC) and new approach methods (NAMs) are valuable approaches for drug discovery and extrapolation to humans. Preclinical studies require the development of in vitro drug efficacy and safety assessment based on the function of the neural network. A microelectrode array (MEA) can effectively and noninvasively measure the electrical activity of a human iPSC-derived neural network at multiple points. In this chapter, we begin by focusing on the prediction of seizure liability for drugs. First, we describe the relationship between predicting seizure risk using principal component analysis based on in vitro neural activity data and the concentrations of cerebrospinal fluid (CSF) in vivo rats. Furthermore, we describe an AI analysis method using raster plot images to predict seizure liability for drugs using the obtained data of neural activities. The neurotoxicity of compounds includes not only central neurotoxicity but also peripheral neuropathy. We introduce the responsiveness of TRP channels using MEA measurement of human iPSC-derived sensory neurons and the increase in cold sensitivity due to anticancer drugs. The transition from an in vitro assessment system to an in vivo one presents a future challenge. Human brain organoids with a three-dimensional structure can be effective in approaching this in vitro-to-in vivo extrapolation (IVIVE). Finally, we introduce a frequency analysis method that enables the measurement of drug responsiveness of brain organoids to draw comparisons with in vivo electroencephalography (EEG).