Background: The bark of Entandrophragma cylindricum (Meliaceae) is used in traditional Cameroonian medicine to treat jaundice, gastric ulcers, wounds, pain, and malaria. Chronic consumption of ''Odontol,'' a traditional Cameroonian artisanal alcohol, is associated with hepatotoxicity and progressive neurological impairment. This study evaluated the neuroprotective, anti-amnesic, and antidepressive potentials of the aqueous bark extract of E. cylindricum in a rat model of ''Odontol''-induced neurotoxicity. Methods: Following collection and extraction of the plant, HPLC analysis was performed to determine the compounds present in the plant extract. The aqueous extract was administered concomitantly with ''Odontol'' at 200, 300, and 400 mg/kg/day for 41 days in male Wistar rats, with silymarin (100 mg/kg) as reference drug. Behavioral assessments included open field test, forced swim test, novel object recognition test, and Morris water maze test. On day 42, blood, liver, and hippocampal tissues were collected for biochemical, oxidative stress, neuroinflammatory, and histological analyses. CBdock2 and Biovia discovery studio 2024 were used to perform molecular docking between Entandrophragma cylindricum identified compounds and target proteins GABAr A, NMDA receptor AchE and CaMK. Results: ''Odontol'' induced significant anxiety-like behavior, increased immobility, and cognitive deficits. Hippocampal analysis revealed elevated Ca²⁺, serotonin, TNF-α, IL-1β, malondialdehyde, and nitrite, and reduced GABA, acetylcholine, BDNF, glutathione, catalase, and magnesium. Histology showed neuronal necrosis and reduced cell density in CA1, CA3, and dentate gyrus regions. Extract at 300 and 400 mg/kg significantly attenuated all behavioral, biochemical, and histological alterations compared to silymarin. Although molecular docking remains predictive, compounds such as rutin and quercetin bound to target proteins with significant binding energies, thereby potentially modulating the activity of these proteins to protect against Odontol-induced neurotoxicity. Conclusion: E. cylindricum aqueous bark extract exerts antioxidant, anti-inflammatory, anti-amnesic, and antidepressive effects, likely through its biochemical constituents.
