Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis

Abstract

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.

TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

“…However, because MMP-9 activation may be considered a marker of neuroinflammation, effects on MMP-9 and perhaps other specific inflammatory mediators influenced by TNF/Fas may have contributed to differences in outcome between the two groups. Previous work has shown that MMP-9 mediates brain edema, motor impairment, and tissue damage after CCI in mice (Wang et al, 2000), and contributes to spatial learning deficits after meningitis in rats (Leib et al, 2001). Thus, MMP-9 may be one mechanistic link between TNFa/Fas signaling and histopathological and functional outcome after CCI.…”

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

“…Gelatinases (MMP-2 and MMP-9) have shown to induce BBB breakdown and facilitate leukocyte extravasation in experimental bacterial meningitis 49 , furthermore, patients with bacterial meningitis present high concentrations of MMP-939 and MMP-8 in the CSF, indeed, high concentrations of MMP-9 were correlated with risk factor for the development of postmeningitis neurological sequelae 48 . In a rat model, adjuvant treatment with dexamethasone resulted in a lower MMP-9 mRNA 50 , in addition, combining the MMP and TNF-α inhibitors led to a decrease incidence of the seizures and mortality, furthermore, neuronal necrosis in the cortex and apoptosis in the hippocampus were attenuated in rats submitted by pneumococcal meningitis 51 .…”

Matrix metalloproteinases in neuroinflammation

“…Production of MMPs has been associated with the BBB damage in experimental models of bacterial meningitis induced by intracisternal injection of bacteria (Leib et al, 2001). The opening of the BBB could be blocked by the use of the MMP inhibitor, BB-1101.…”

“…Treatments in several animal models of neurological diseases have produced encouraging results. These include intracerebral hemorrhage, experimental allergic neuritis, delayed hypersensitivity, and bacterial meningitis (Rosenberg and Navratil, 1997;Hughes et al, 1998;Lapchak et al, 2000;Leib et al, 2001).…”