Developmental and behavioral toxicity assessment of opicapone in zebrafish embryos

The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-Omethyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 mu M) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.