A network pharmacology approach validates resveratrol’s in vivo neuroprotective effects against neurotoxic metals-induced cognitive decline
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Abstract
Objective: To investigate the neuroprotective effects of resveratrol against combined neurotoxicity induced by aluminum (Al), lead (Pb), and arsenic (As) using integrated in-silico and in-vivo approaches.
Methods: Thirty adult male Sprague–Dawley rats (10–12 weeks; 180–250 g) were randomized into three groups (n=10 each): control, metal mixture (Al+As+Pb; 25 mg/kg/day, oral), and metal mixture plus resveratrol (20 mg/kg/day in feed) for 60 days. Cognitive performance was assessed using the Y-maze and Morris water maze (MWM). Gene expression of synaptophysin, PSD-95, and CaMKIV in cortex and hippocampus was evaluated by qPCR using the 2^-ΔΔCT method. In-silico target prediction and network pharmacology were performed using Swiss Target Prediction, CTD, and GeneCards; intersecting targets were analyzed via STRING and Cytoscape, followed by GO/KEGG enrichment (DAVID/ShinyGO). Molecular docking (AutoDock Vina) assessed binding of resveratrol with IL6, TNF, IL1-β, synaptophysin, CaMKIV, and PSD-95.
Results: Network pharmacology identified 269 intersecting targets; hub genes included IL6, TNF, and IL1-β. Enrichment analysis highlighted pathways related to inflammation, apoptosis regulation, PI3K-Akt, MAPK, and neurodegeneration. Docking showed strong affinity with CaMKIV (−8.1 kcal/mol) and moderate affinity with IL6 (−6.8), IL1-β (−6.9), and PSD-95 (−6.5). In-vivo, the metal mixture impaired memory in Y-maze and MWM, while resveratrol significantly improved performance. Metal exposure downregulated synaptophysin, PSD-95, and CaMKIV expression in cortex and hippocampus; resveratrol partially to markedly restored expression.
Conclusion: Resveratrol mitigated Al/As/Pb-induced neurotoxicity, improving cognitive performance and synaptic gene expression, potentially through multi-target modulation of inflammatory and neurodegenerative pathways.
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Funding data
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Higher Education Commision, Pakistan
Grant numbers NRPU Grant Number 9780
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