Multi-Target Neuroprotection by Syzygium aromaticum Ethyl Acetate Fraction Against Mercuric Chloride-Induced Hippocampal Toxicity: Insights from Network Pharmacology, Molecular Docking, and In Vivo Evaluation

Mercury remains a pervasive environmental neurotoxicant strongly implicated in hippocampal oxidative injury and dementia-related cognitive decline, yet safe multi-target agents against its neurotoxicity remain limited. This study investigated the neuroprotective potential of the Syzygium aromaticum (clove) ethyl acetate fraction (SEAF) against mercuric chloride (HgCl 2 )-induced hippocampal neurotoxicity using an integrated network pharmacology, molecular docking, and in vivo evaluations. GC-MS profiling of SEAF (5.29% yield) identified 13 abundant metabolites, dominated by eugenyl acetate, eugenol, 14-hydroxycaryophyllene, and β-caryophyllene. Consensus screening with SwissADME and ADMETlab 3.0 identified eugenyl acetate, benzyl benzoate, and 1-methylcyclododecanol as blood-brain barrier (BBB)-permeant. Network pharmacology integrating SwissTargetPrediction, TargetNet, GeneCards, and the Therapeutic Target Database revealed 16 overlapping dementia-associated targets, with NFKB1 emerging alongside other genes as the principal hub governing nuclear receptor signalling, oxidative stress, and neuroinflammation pathways. Molecular docking against NMDA, GABA_A, NF-κB1, and acetylcholinesterase receptors showed eugenyl acetate and benzyl benzoate consistently exhibited the strongest and most consistent binding affinities among the BBB-permeant metabolites. In vivo , pretreatment with SEAF (250–1000 mg/kg) dose-dependently attenuated HgCl₂-induced deficits in object location and Y-maze performance, restored hippocampal superoxide dismutase and catalase activities, reduced malondialdehyde levels, and preserved CA1/CA3 pyramidal cell architecture, with the 1000 mg/kg dose approximating Vitamin E and control groups. These convergent computational and experimental findings identify SEAF as a multi-target neuroprotective agent that mitigates mercury-induced hippocampal neurodegeneration through coordinated antioxidant, anti-inflammatory, and neurotransmission-modulating mechanisms, supporting its further development as a candidate nutraceutical neuroprotectant against heavy-metal-associated dementia risk.