Mannitol-facilitated entry of vancomycin into the central nervous system inhibits neuroinflammation in a rat model of MRSA intracranial infection by modulating brain endothelial cells.

BACKGROUND

The present study aims to investigate whether mannitol facilitates central nervous system (CNS) entry of vancomycin and alleviates methicillin-resistant Staphylococcus aureus (MRSA) intracranial infection.

METHODS

Blood-brain barrier (BBB) permeability was assessed by measuring the concentration of sodium fluorescein (NaF) in the brain tissues of rats and fluorescein isothiocyanate-dextran (FITC-dextran) in a single-cell layer model. Neutrophil infiltration in the brain tissue, inflammatory cytokine levels in the serum, neurological function, and 7-day survival rates were used to evaluate therapeutic effects of mannitol and vancomycin in MRSA-infected rats. Syndecan-1 and filamentous actin (F-actin) levels were measured, and the relationship between F-actin and the endothelial glycocalyx layer (EGL) was explored via the depolymerization agent cytochalasin D and the polymerization agent jasplakinolide.

RESULTS

Following mannitol administration, the NaF and vancomycin concentrations in the brain tissue increased rapidly within 5 min and remained stable for 30 min, indicating that mannitol increased BBB permeability for 30 min. In vitro, mannitol treatment led to significantly greater FITC-dextran permeation through a single-cell layer compared to controls. In the MRSA intracranial infection model, rats treated with mannitol and vancomycin simultaneously presented less inflammation, improved neurological function, and increased 7-day survival rate compared to rats treated with vancomycin and mannitol at 10-hour intervals. Further experiments revealed that mannitol decreased the expression of syndecan-1 in brain tissues, which was confirmed by in vitro experiments showing that mannitol significantly decreased syndecan-1 via F-actin depolymerization.

CONCLUSION

Mannitol may enhance the therapeutic efficacy of vancomycin against intracranial MRSA infection by decreasing the endothelial glycocalyx of the BBB via F-actin depolymerization.