This study investigated the protective effect of quercetin against cyclophosphamide‐induced immunosuppressive indoleamine 2,3‐dioxygenase (IDO) via the mechanism of oxidative‐inflammatory stress and behavioral indices. Cyclophosphamide (CYP) was administered to male Wister rats at a dose of 100 mg/kg with or without quercetin 50 mg/kg every other day for 7 days. Experimental techniques including western blotting, immunohistochemistry analysis, and inflammatory and oxidative stress marker assays were carried out. We also conducted behavioral analyses such as open field, tail suspension, and Y‐maze tests for cognitive assessment. The results indicated that quercetin attenuated oxidative‐inflammatory stress induced by CYP in the hippocampus and cerebral cortex of male Wister rats by augmenting the activities of antioxidant enzymes and suppressing lipid peroxidation as well as inflammatory mediators such as interleukin‐6 and interferon‐γ. Concomitantly, quercetin partially prevented the alteration in brain tissue histological architecture and mitigated the activities of IDO/tryptophan 2,3‐dioxygenase (TDO) and protein expression of IDO1. This was corroborated by the IDO‐quercetin model obtained in silico, revealing a favorable inhibitory interaction between quercetin and the enzyme. Finally, the results of behavioral tests suggested that quercetin significantly prevented the depressive‐like posture of the CYP‐treated rats. Our study for the first time revealed that quercetin ameliorates the effect of CYP‐instigated IDO/TDO activities in the cerebral cortex and hippocampus via restoration of antioxidant enzymes and preventing oxidative‐inflammatory stress.

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