Bryophyllum pinnatum (L.) Pers. Modulates Multiple Neuroprotective Targets in Alzheimer's Disease: Evidence from...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, with limited therapeutic options and adverse effects associated with long-term pharmacological treatments. This study investigated the neuroprotective potential of Bryophyllum pinnatum (B. pinnatum) through integrative in silico and in vivo approaches. Network pharmacology and pathway enrichment analyses (KEGG, Cytoscape 3.10.1) were used to identify compound-target network association. Molecular docking using AutoDock Vina and molecular dynamics (MD) simulations for 200 ns using GROMACS were executed to assess the stability of the key ligands and targets. Cognitive impairment was induced in Wistar rats using scopolamine (1 mg/kg, i.p.). Animals were treated with B. pinnatum hydroalcoholic leaf extract (200 and 400 mg/kg, p.o.) and donepezil (3 mg/kg, i.p.) for 30 days. Cognitive and motor functions were evaluated via Morris water maze, elevated plus maze, locomotor activity, and grip strength tests. Biochemical assays measured acetylcholinesterase (ACHE) activity, β-amyloid (Aβ) levels, glutathione, and lipid peroxidation. Histopathological analysis of brain tissue assessed neuronal integrity. In silico analyses identified multiple phytoconstituents involved in AD-relevant pathways, including MAPK, PI3K-Akt, and cholinergic signaling. Diosmin exhibited high binding affinities to ACHE (-10.3 kcal/mol) and MAO-B (-11.2 kcal/mol), with stable binding confirmed via MD simulations. In vivo, B. pinnatum significantly improved cognitive performance, motor coordination, and antioxidant status while reducing Aβ aggregation and ACHE activity (p < 0.05). Histological findings showed reduced neuronal degeneration and neuroinflammation. These results highlight the multitarget neuroprotective potential of B. pinnatum, with diosmin emerging as a promising plant-derived candidate for AD therapeutics.