Evaluation of developmental toxicity of safinamide in zebrafish larvae (Danio rerio)

Monoamine oxidase-B (MAO-B), as a principal metabolizing enzyme, plays important roles in the metabolism of catecholamines and xenobiotics in the central nervous system and peripheral tissues. Safinamide, the third-generation reversible MAO-B inhibitor, has potential to alleviate many neurological diseases such as Parkinson's disease (PD) and depression. Exposure to clinical psychotropic drugs often has adverse effects on fetuses. Currently, a variety of studies of safinamide focus on its curative effect and pharmacological effect, while its side effect of embryonic development is barely studied. In this study, we used zebrafish as a model to evaluate the embryonic developmental toxicity of safinamide. Our results revealed that higher concentrations (30 μM) of safinamide treatment caused a decrease in hatching rate and an increase in malformation and mortality in zebrafish larvae. Meanwhile, we observed that lower safinamide exposure (10 μM) increased the body length of zebrafish larvae and resulted in hyperactivity-like behaviors. In addition, an increased trend in dopamine (DA) level was found in 3.3 μM and 10 μM safinamide-exposed groups. Transcriptome analysis identified that safinamide exposure may disturb a variety of physiological processes such as neuroactive ligand-receptor interaction signaling pathway. In summary, our study reveals that safinamide may cause developmental defects in zebrafish larvae and provides insights into its toxic reactions in early develoment.