Multi-target therapeutic potential of Antidesma montanum blume leaf extract against cognitive impairment: an integrated computational and experimental pharmacology approach

Background and aim Cognitive impairment is a major functional consequence of neurological and neurodegenerative disorders and is particularly prominent in Alzheimer’s disease (AD). Multiple mechanisms, including cholinergic dysfunction, oxidative imbalance, neuroinflammation, and neuronal injury, contribute to cognitive decline. Antidesma montanum Blume (family Phyllanthaceae) is a traditionally used medicinal plant rich in bioactive phytoconstituents; however, its therapeutic potential to alleviate chemically induced cognitive impairment remains insufficiently explored. Hence, the present study aimed to investigate the cognitive-enhancing potential of the ethanolic leaf extract of A. montanum Blume in an aluminium chloride (AlCl₃)-induced cognitive impairment model in rats. Study design and methods The phytomolecules in the leaf were profiled by HR-LCMS, screened for blood-brain barrier permeability and drug-likeness, and analysed by network pharmacology, molecular docking, and a 200 ns molecular dynamics simulation with MM-PBSA analysis. The extract (100, 200, and 400 mg/kg) was evaluated for its effects on AlCl₃-induced cognitive impairment using the Elevated Plus Maze and Y-maze, supported by cholinesterase and antioxidant assays and histopathological assessment. Results Computational analyses indicated that several constituents possess favourable drug-like properties and interact with AD-implicated targets, including AKT1, MAPK3, and TNF. The extract produced a dose-dependent improvement in learning and memory, a marked reduction in acetylcholinesterase and butyrylcholinesterase activity, and restoration of superoxide dismutase and catalase activity, with the 400 mg/kg dose producing the largest effect, approaching, but not matching, that of rivastigmine in every endpoint. Histopathology confirmed preservation of hippocampal neuronal architecture in treated groups. Conclusion A. montanum exerts beneficial effects on cognitive function by modulating cholinergic and oxidative stress pathways, as well as key neuronal survival signalling pathways. These results support its potential as a candidate for further investigation in the management of cognitive impairment associated with neurodegeneration.