Effects of Metronidazole on the Functional Properties of Human iPSC-derived Neurons
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Metronidazole is a widely used nitroimidazole antibiotic generally considered safe; however, accumulating clinical reports have raised concerns about its neurotoxic potential, particularly under prolonged or high-dose exposure. This study aimed to investigate the functional effects of metronidazole on neuronal activity using human-induced pluripotent stem cell (hiPSC)-derived neurons combined with multi-electrode array (MEA). Neurons were treated with metronidazole at clinically relevant concentrations (0, 4, 20, and 100 µg/ml) for 1 hr, and electrophysiological parameters including mean firing rate, burst frequency, and network synchrony were quantitatively analyzed. At the intermediate concentration of 20 µg/ml, neuronal excitability was significantly increased, potentially reflecting GABAergic inhibition or monoaminergic dysregulation. In contrast, the highest concentration 100 µg/ml did not enhance activity further and instead elicited a slight reduction, indicative of functional suppression or cytotoxic effects. This study demonstrates the utility of MEA-based hiPSC neuronal models as a sensitive platform for detecting sublethal neurotoxic effects of clinically relevant drugs and provides mechanistic insights into the neurophysiological impact of metronidazole.
Abstract
Metronidazole is a widely used nitroimidazole antibiotic generally considered safe; however, accumulating clinical reports have raised concerns about its neurotoxic potential, particularly under prolonged or high-dose exposure. This study aimed to investigate the functional effects of metronidazole on neuronal activity using human-induced pluripotent stem cell (hiPSC)-derived neurons combined with multi-electrode array (MEA). Neurons were treated with metronidazole at clinically relevant concentrations (0, 4, 20, and 100 µg/ml) for 1 hr, and electrophysiological parameters including mean firing rate, burst frequency, and network synchrony were quantitatively analyzed. At the intermediate concentration of 20 µg/ml, neuronal excitability was significantly increased, potentially reflecting GABAergic inhibition or monoaminergic dysregulation. In contrast, the highest concentration 100 µg/ml did not enhance activity further and instead elicited a slight reduction, indicative of functional suppression or cytotoxic effects. This study demonstrates the utility of MEA-based hiPSC neuronal models as a sensitive platform for detecting sublethal neurotoxic effects of clinically relevant drugs and provides mechanistic insights into the neurophysiological impact of metronidazole.