Favipiravir, an antiviral flu drug used in COVID-19 management, was selected to study the adverse effects on neuropsychological stress and neurobehavior in an adult zebrafish model. The ability of vitamin D to act as a supplement and counteract the side effects was studied. Exposure of favipiravir may affect the gut-liver-brain axis and cause neurobehavioral and neuropsychological changes along with increase in oxidative stress parameter. Vitamin D might provide supplementary actions against them and restore homeostasis. Zebrafish were exposed to three different sub-lethal concentrations of the drug (60.45 mg/L, 6.05 mg/L, 0.60 mg/L) based on LC50, and additional exposure group of combination of sub-lethal concentrations of favipiravir with vitamin D (3000 IU/g) were carried out. Acute exposure (60.45 mg/L, 6.05 mg/L, 0.60 mg/L) was given for 5 days, and then exposure was ceased, followed by maintenance of the zebrafish for 10 days to study the long-term effects of favipiravir. The highest concentration of favipiravir (60.54 mg/L) showed a significant decrease in oxidative stress parameters-superoxide dismutase, catalase, glutathione-S-transferase activities and increased activity of antioxidant enzymes with vitamin D and favipiravir (60.45 mg/L) groups was observed. Favipiravir (60.45 mg/L) showed reduced BDNF gene expression, serotonin levels, and AChE activity. There was an upregulation of CRH and TSHβ gene and an increase in whole body cortisol levels. Exposure to favipiravir induces gut dysbiosis, leading to an increase in abundance of Proteobacteria and a decrease in Fusobacteriota, altering the gut-brain axis. The changes cause reduced locomotion, impaired memory function, anxiety, and depression. Therefore, favipiravir exposure in sub-lethal doses causes neurotoxicity in the zebrafish model, and vitamin D showed a supplementary effect by restoring homeostasis.
