Similarity between the responses to antibacterial drugs in human iPSC-derived neurons and the classification of antibacterial drug encephalopathy in clinical

Abstract

Human iPSC-derived neurons are expected to be applied to toxicity evaluations in nonclinical studies. Microelectrode array (MEA) measurement system is suitable to evaluate the electrophysiological responses to drugs. In this study, we examined its application for the risk assessment of antibiotic associated encephalopathy (AAE). AAE can be classified into three clinical encephalopathy types: encephalopathy accompanied by seizures; encephalopathy characterized by psychosis; and encephalopathy accompanied by cerebellar signs. We investigated whether the electrophysiological responses to antibiotics in human iPS cell-derived neural network classify into three clinical types. Human iPS cell-derived neurons and astrocytes were co-cultured on MEA. More than 10 antibiotics were cumulative administered in culture samples. We classified the responses to antibiotics by multivariate analysis. Cephalosporins and penicillins, which are classified into type 1 AAE, increased the firing frequency and synchronized activities of the neural network. These results were consistent with seizures of type 1 AAE in clinically reported. Quinolones, macrolides, and procaine penicillin, which are classified into type 2 AAE in clinically reported, showed a different response from type 1. These results suggested that the responses to antibiotics in human iPSC-derived neurons and the classification of antibiotics encephalopathy in clinical are correlated. MEA assay coupled with human iPSC-derived neurons and our multivariate analysis are useful for the risk prediction and risk classification of AAE.