Quercetin protects against neuronal toxicity by activating the PI3K/Akt/GSK-3β pathway in vivo models of MPTP-induced Parkinson's disease

Background Quercetin is a flavonoid commonly found in various fruits, vegetables, and grains. Studies have demonstrated that quercetin may help protect neuronal cells from damage caused by neurotoxins associated with Parkinson's disease, however, the underlying mechanism remains unclear. Aim The current study aimed to investigate the neuroprotective effects of quercetin in MPTP-induced Parkinson's disease mouse models and elucidate its mechanistic role in modulating the PI3K/Akt/GSK-3 beta signaling pathway. Materials and methods Male C57BL/6 mice were divided into control, MPTP, quercetin, and MPTP + quercetin groups. The protective effects of quercetin on Parkinson's disease in mice were evaluated using animal behaviour analysis, histopathological examination, and immunofluorescence staining. Subsequently, network pharmacology was utilized to determine the primary target sites of quercetin in Parkinson's disease. Finally, western blotting and molecular docking techniques were applied to validate the identified targets. Results Quercetin significantly improved motor deficits in MPTP mice, reduced neuronal atrophy, and preserved TH+ dopaminergic neurons. Western blotting analysis revealed quercetin upregulated anti-inflammatory IL-10 (p < 0.01) and TGF-beta (p < 0.01) while suppressing pro-inflammatory IL-1 beta (p < 0.01) and iNOS (p < 0.01). It activated the PI3K/Akt/GSK-3 beta pathway by increasing phosphorylation of PI3K (p < 0.01), Akt (p < 0.01), and GSK-3 beta (p < 0.01). Quercetin also elevated anti-apoptotic Bcl-2 (p < 0.01) and reduced pro-apoptotic Bax (p < 0.01) and Caspase-9 (p < 0.01). Molecular docking confirmed strong binding between quercetin and PI3K/Akt/GSK-3 beta (binding energies: -6.44 to -5.24 kcal/mol). Conclusion Quercetin alleviates Parkinson's disease pathology by inhibiting neuroinflammation, reducing apoptosis, and activating the PI3K/Akt/GSK-3 beta pathway. These findings underscore its potential as a multi-target therapeutic agent for Parkinson's disease.