Therapeutic effect of taxifolin on bacterial meningitis associated with inhibition of PI3K/AKT and MAPK signalling

Abstract

Background

Bacterial meningitis (BM) represents a severe infectious disease characterized by high mortality and neurological sequelae. The increasing prevalence of antimicrobial resistance has compromised antibiotic therapies, emphasizing an urgent need for alternative treatments. Taxifolin (TAX), a naturally occurring flavonoid, exhibits multiple bioactivities, yet its role in BM remains unknown.

Purpose

This study investigated the therapeutic effects of TAX in BM and explored its underlying molecular mechanisms.

Study design and methods

Using both in vitro and in vivo approaches, we established BM models with extraintestinal pathogenic Escherichia coli and Streptococcus suis. The therapeutic efficacy of TAX was assessed through comprehensive analyses of pathological changes and inflammatory responses. Molecular mechanisms were investigated using multiple approaches, including network pharmacology, Western blotting, drug affinity-responsive target stability assay, and cellular thermal shift assay.

Results

TAX significantly inhibited bacteria-induced cell death in microglia and brain endothelial cells, reduced microglial inflammatory responses, and protected endothelial tight junction proteins in vitro. In mice, TAX markedly reduced mortality, alleviated tissue damage, and suppressed inflammatory responses. The protective effects of TAX were associated with the inhibition of PI3K/AKT and MAPK pathways, with AKT identified as its direct target.

Conclusions

Our findings identify TAX as a potential therapeutic agent for BM treatment, with its protective effects associated with the inhibition of PI3K/AKT and MAPK pathways. These results provide a foundation for the further development of TAX-based interventions against BM.