A network pharmacology approach and experimental validation to investigate the neuroprotective mechanism of quercetin against alcoholic brain injury via the JNK/P38 MAPK signaling pathway

Abstract

Objective

Alcoholic brain damage (ABD) is a progressive neurodegenerative disorder resulting from prolonged and excessive alcohol consumption, characterized by neuronal injury and cognitive decline. Currently, effective therapeutic strategies remain limited. Quercetin, a natural flavonoid, has demonstrated robust antioxidative, anti-inflammatory, and neuroprotective properties, suggesting its potential utility in ABD management. This study aimed to elucidate the molecular mechanisms underlying quercetin's therapeutic effects on ABD, specifically focusing on its regulatory role in the JNK/P38 MAPK signaling pathway, a critical mediator involved in neuroinflammation and apoptosis. Our findings provide mechanistic insights into the protective effects of quercetin and underscore its promise as a novel therapeutic agent targeting neuronal injury pathways associated with alcoholic brain damage.

Methods

The components and targets of QE and ABD were identified from multiple databases, and potential targets and pathways were predicted using protein-protein interaction (PPI) network analysis and pathway enrichment analysis. Molecular docking was then employed to validate the predicted results. In vivo, an EtOH-induced ABD rat model was established, while in vitro, EtOH-induced BV2 microglial cells were used to investigate the anti-inflammatory and anti-apoptotic effects of QE. The potential mechanisms of QE were further validated through both in vivo and in vitro experiments.

Results

KEGG analysis indicated that the JNK/P38 MAPK signaling pathway is likely associated with the protective effects of QE against ABD. Molecular docking results demonstrated that QE effectively binds to key proteins. QE significantly reduced brain tissue damage in ABD rats, and molecular biology analyses revealed that QE inhibited the protein expression of inflammatory cytokines in ABD and reduced oxidative stress levels in BV2 cells. Additionally, QE markedly decreased the protein expression levels of phosphorylated JNK and P38.

Conclusion

The study results indicate that QE significantly mitigates the progression and severity of alcoholic brain damage (ABD), with its anti-inflammatory and neuroprotective effects associated with the downregulation of the JNK/P38 MAPK pathway.