Dexamethasone regulation of matrix metalloproteinase expression in experimental pneumococcal meningitis

Abstract

Accumulating evidences have demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis. MMPs facilitate leukocyte extravasation and brain edema by degradation of extracellular matrix components. Dexamethasone as adjunctive therapy to antibiotics has shown to have beneficial effects on pathophysiological changes and neurological outcome in children with meningitis and in animal models. However, the role of dexamethasone in the pathophysiology of pneumococcal meningitis is still unknown. The effects of antibiotics on MMPs in bacterial meningitis have not been evaluated so far. We have therefore intended to investigate the induction and expression of MMPs with special emphasis on the regulation of MMPs by dexamethasone and antibiotics in therapy of pneumococcal meningitis. In the present study, the expression of MMP-9 and MMP-2 mRNA in the brain of rats and the activity of MMP-9 and MMP-2 in the CSF of rats have been determined during the course of experimental bacterial meningitis and after treatment with an antibiotic plus dexamethasone. In the brain tissue of rats with Streptococcus pneumococcal meningitis, MMP-9 mRNA was obviously up-regulated after inoculation for 24 h (p<0.01) and then declined but was still greater than that in the brains of control rats after inoculation for 4 days (p<0.05) while the expression of MMP-2 remained at basal level. The expression of MMP-9 in the brains of rats inoculated with Streptococcus pneumoniae and treated by antibiotic was dose-dependent, up-regulated (p<0.01) but down-regulated after treatment with an antibiotic plus dexamethasone (p<0.01). However, the expression of MMP-9 mRNA did not change in the rats inoculated with sterile saline and treated with an antibiotic. The zymographic activity of MMP-9 and MMP-2 showed similar changes. The results indicated that the expression of MMP-9 mRNA and its activity might be increased after antibiotic treatment and inhibited after treatment with antibiotics plus dexamethasone; dexamethasone might have a beneficial effect on bacterial meningitis via down-regulation of the expression of MMP-9.