Neurotoxicity study of cenobamate-induced zebrafish early developmental stages

Cenobamate (CNB) is a novel anti-seizure medication with significant efficacy in treating epilepsy. However, in clinical trials, the most common adverse reactions observed in patients are central nervous system (CNS) symptoms. In animal studies, administration of CNB during pregnancy or lactation has been associated with adverse effects on neurodevelopment in offspring. To optimize the clinical use of CNB, we investigated the neurotoxicity of different concentrations of CNB (10, 20, 40, 80, and 160 μM) on zebrafish embryos. Following exposure, zebrafish embryos exhibited abnormal phenotypes such as shortened body length, impaired yolk sac absorption, and decreased heart rate. Behavioral experiments showed that CNB caused abnormal movements such as decreased spontaneous tail curling frequency, shortened total movement distance, and reduced average movement speed. We also found that CNB leads to increased acetylcholinesterase (AChE) activity levels in zebrafish embryos, along with differential expression of neurodevelopment-related genes such as nestin, gfap, synapsin IIa, and gap43. In summary, our research findings indicated that CNB may induce developmental and neurotoxic effects in zebrafish embryos by altering neurotransmitter systems and the expression of neurodevelopmental genes, thereby influencing behavior. This study will provide information for the clinical use of CNB, aiming to benefit more epilepsy patients through its appropriate administration.