Syzygium aromaticum Attenuates Cerebellar Oxidative Stress: An Integrated in silico, in vitro, and in vivo Evaluation of Multi-Target Antioxidant Mechanisms

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Introduction: The central role of oxidative stress in neuronal injury and the progression of neurological disorders underscores the need to identify multi-target agents capable of restoring redox homeostasis. This study evaluated the antioxidant and pharmacological potential of Syzygium aromaticum ethyl acetate fraction (SEAF) using integrated phytochemical, computational, and experimental approaches. Methods: GC-MS was used to characterize the phytochemical composition of the ethyl acetate fraction of Syzygium aromaticum (SEAF). Thirteen phytometabolites with relative peak areas ≥ 1.0% were selected for ADME-Tox profiling and molecular docking against monoamine oxidase B (MAO-B) and 5-lipoxygenase (5-LOX). In vitro antioxidant assays, acute oral toxicity testing, and in vivo evaluation of cerebellar oxidative stress biomarkers were subsequently performed. Results: GC-MS identified eugenyl acetate (43.08%), eugenol (18.86%), and β-caryophyllene (1.64%) as the predominant metabolites. The prioritized phytometabolites exhibited favorable predicted ADME-Tox profiles and notable binding energies for MAO-B (up to − 8.4 kcal/mol) and 5-LOX (up to − 6.8 kcal/mol), involving key interactions with HIS367 and HIS372 in MAO-B and GLN363, TYR435, and CYS172 in 5-LOX, comparable to the standard ligands. Although ascorbic acid exhibited greater radical-scavenging and ferric-reducing potencies than SEAF in the DPPH and FRAP assays, respectively, SEAF showed higher total antioxidant activity than ascorbic acid. In vivo, SEAF administration was relatively safe up to 2000 mg/kg and significantly increased cerebellar superoxide dismutase and catalase activities while reducing malondialdehyde levels in HgCl 2 -treated mice, with effects comparable to vitamin E. SEAF preserved cerebellar cortex histoarchitecture and Nissl substance in Purkinje cells against mercuric chloride-evoked oxidative damage. Conclusion: Syzygium aromaticum exhibited potent antioxidant effects through combined radical scavenging, enzymatic enhancement, modulation of oxidative stress-related targets, and preservation of cerebellar histoarchitecture, supporting its potential as a candidate for further preclinical development. Keywords: antioxidants, cerebellum, oxidative stress, phytomedicine, Syzygium aromaticum

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