Aslam_2025_J.Ethnopharmacol_359_121052

ETHNOPHARMACOLOGICAL RELEVANCE: Prosopis cineraria is traditionally used to enhance cognitive function and manage mental disorders. Its stem bark is valued in ethnomedicine, but its potential anti-Alzheimer's disease (AD) effects are scientifically unexplored. AIM OF THE STUDY: This research has examined the neuroprotective effects of the ethyl acetate fraction of P. cineraria bark (Pc-EA) against AlCl(3)-induced AD pathology, focusing on behavioral, biochemical, histological, and molecular outcomes. MATERIAL AND METHODS: Diseased rats were treated with Pc-EA (30, 100, and 300 mg/kg) for 42 days. Cognitive and affective functions were evaluated with behavioral tests on days 29-42. Biochemical assays measured oxidative stress and cholinesterase activity, while RT-PCR quantified neuroinflammatory markers. Histopathological examination was performed to evaluate the integrity of hippocampal regions. Bioactive compounds were identified by phytochemical profiling (HPLC, GC-MS), and molecular docking was performed to assess binding interactions with acetylcholinesterase. RESULT: AlCl(3) exposure impaired memory, augmented anxiety and depression-like behavior, elevated oxidative stress, AChE activity, and induced hippocampal neurodegeneration with upregulated BACE-1, Tau, Caspase-3, and NF-kappaB alongside downregulated BDNF. These changes were reversed by Pc-EA (100 mg/kg), which enhanced cognitive function, restored antioxidant defense, inhibited AChE and neuroinflammatory markers, and maintained hippocampal architecture. Bioactive phytoconstituents (chlorogenic acid, kaempferol, quercetin), which exert anti-amyloidogenic, antioxidant, anti-inflammatory, and acetylcholinesterase inhibitory effects, were identified by HPLC and GC-MS, and their potential roles were corroborated via in silico validation. CONCLUSION: Pc-EA demonstrated multi-targeted neuroprotection in AlCl(3)-induced AD, which is consistent with ethnomedicinal claims. These findings indicate P. cineraria as a potential modulator of AD through antioxidant, anti-inflammatory, anti-amyloidogenic, and neurotrophic mechanisms.