Multimodal evaluation of nitazoxanide as an antidepressant: behavioral, biochemical, and molecular docking insights

This study aimed to evaluate the antidepressant potential of Nitazoxanide (NTZ), an antiprotozoal drug with known anti-inflammatory and neuroprotective properties, in a chronic unpredictable mild stress (CUMS)-induced mice model of depression. NTZ was administered at doses of 75, 150, and 300 mg/kg, and its effects were assessed through a series of behavioral tests, including the forced swim test, tail suspension test, actophotometer test, and social interaction test. NTZ treatment at 150 and 300 mg/kg significantly improved behavioral and biochemical outcomes, relieving depressive-like symptoms and restoring neurochemical balance. Significant relief of depressive-like symptoms was observed following NTZ treatment. To understand the underlying mechanisms, we examined the modulation of neuroinflammatory and neurotransmitter pathways. NTZ treatment increased phosphoinositide 3-kinase (PI3K) and serotonin (5-HT) levels while decreasing pro-inflammatory markers such as nuclear factor kappa B (NF-κB) and interleukin-1 beta (IL-1β), indicating potent anti-inflammatory and neuroprotective effects. Additionally, molecular docking analysis confirmed NTZ's effective binding affinity to depression-related target proteins 8DP0 and 1K3Z, with binding energies of - 11.81 and 29.878 kcal/mol, respectively. These findings indicate that modulation of the PI3K/Akt/NF-κB signaling pathway mediates NTZ's antidepressant effects. Overall, our study provides compelling evidence that NTZ produces significant antidepressant activity by targeting key inflammatory and neuroprotective pathways, highlighting its potential as a novel therapeutic option for depression and supporting the need for further long-term studies to evaluate its efficacy and safety.