Behavioral and biochemical alterations in zebrafish model suggests AChE as a potential target for cytarabine neurotoxicological effects

<title>Abstract</title> Due to their general cytotoxic effects, anticancer drugs pose a great risk to aquatic species, yet they have been among the least studied groups of drugs regarding their environmental impact. The present study aimed to identify the effects of the antileukemia drug cytarabine, also known as cytosine arabinoside (ara-C), on the development and neurobehavior of zebrafish larvae. Zebrafish eggs were exposed to cytarabine to assess survival, embryonic malformations, locomotor activity, DNA damage, and biochemical alterations. No mortality, teratogenicity, or genotoxicity was detected in zebrafish larvae up to 100 mg L-1. However, cytarabine decreased the total distance traveled by zebrafish under dark conditions, suggesting depression-like behavior in treated larvae. Furthermore, it was demonstrated that cytarabine exposure increased lipid peroxidation (LPO) and acetylcholinesterase (AChE) activity, while it inhibited catalase (CAT) activity. Multivariate analysis suggested that both AChE and LPO correlated to behavioral changes, while molecular docking and dynamics simulations suggested a direct binding and stability of cytarabine to AChE. Further analyses of the effects of this anticancer compound in the cholinergic transmission are in progress to allow a better understanding of its neurotoxicity.