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Ethnopharmacological Relevance: Bombax costatum Pellegr. & Vuillet is used traditionally in Northern Cameroon to treat memory impairment, anxiety, insomnia and depression., Aim of the Study: Investigating the effect of Bombax costatum stem bark aqueous extract (BC) on depression associated with amnesia and vascular disorder, using a chronic mild unpredictable stress (CMUS) model in rats for 30 days., Materials and Methods: Sucrose Preference Test (SPT), Forced Swimming Test (FST), corticosteronemia, brain serotonin and dopamine level were evaluated as indices of antidepressant-like effect. The Novel Object Recognition Task (NOR), the Morris Water Maze (MWM) and acetylcholinesterase activity in the hippocampus were also used to verify memory integrity. Oxidative and nitrosative stress markers, the lipid profile and atherogenic index were estimated in blood serum to assess vasoprotective effect. Chlorophenylalanine and haloperidol, were used to delineate the extract's mechanism of action., Results: CMUS induced a decrease in sucrose preference and swimming time in the SPT and FST respectively while BC (27.5 and 55 mg/kg) increased sucrose preference and swimming time. Increments in these parameters were however reversed by the treatment of rats with chlorophenylalanine a serotonin synthesis inhibitor and haloperidol a D2 receptor antagonist. An increase in blood corticosterone level, prefrontal cortex malondialdehyde and nitric oxide concentrations were reversed by the extract. Moreover, BC increased the time spent in the target quadrant of the MWM test and the discrimination index in the NOR test. This was associated with an increase in hippocampus superoxide dismutase and catalase levels, a decrease in acetylcholine esterase level, total blood cholesterol and atherogenicity index compared to CMUS group., Conclusion: Thirty days CMUS induces a depressive state in rats. BC reverses this condition when administered alongside stress exposure. This antidepressive effect is associated with antiamnesic, antioxidant and vasoprotective actions, suggesting its use as a potential candidate in the management of major depressive disorder., (Copyright © 2022 Elsevier B.V. All rights reserved.)