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Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis
1Department of Neurology, Ludwig-Maximilians-University of Munich, Klinikum Brosshadern, Germany.
Abstract:
In this study, we investigated the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis. By using an enzyme immunoassay, high concentrations of MMP-9 were detected in the cerebrospinal fluid (CSF) of adult patients with bacterial meningitis but not in controls, and in patients with Guillain-Barré syndrome. Moreover, we observed significantly elevated concentrations of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CSF of patients with bacterial meningitis, compared with controls. In a rat model of meningococcal meningitis, intracisternal injection of heat-killed meningococci caused a disruption of the blood-brain barrier (BBB), an increase in intracranial pressure, and CSF pleocytosis paralleled by the occurrence of MMP-9 activity in the CSF 6 hours after meningococcal challenge. The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts. In conclusion, our results suggest that MMPs are involved in the alterations of BBB permeability during experimental meningococcal meningitis.
Insights
Matrix metalloproteinases (MMPs) are implicated in bacterial meningitis. MMP-9 and TIMP-1 levels were elevated in patients, and inhibiting MMPs reduced blood-brain barrier disruption in a rat model.
Area of Science:
- Neuroscience
- Pathophysiology
- Biochemistry
Background:
- Bacterial meningitis is a serious infection affecting the central nervous system.
- The role of matrix metalloproteinases (MMPs) in the development of bacterial meningitis is not fully understood.
- Matrix metalloproteinases (MMPs) are enzymes involved in tissue remodeling and inflammation.
Purpose of the Study:
- To investigate the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis.
- To assess the levels of MMP-9 and TIMP-1 in the cerebrospinal fluid (CSF) of patients with bacterial meningitis.
- To evaluate the therapeutic potential of MMP inhibition in an experimental model of meningitis.
Main Methods:
- Enzyme immunoassay was used to measure MMP-9 and TIMP-1 concentrations in human CSF.
- A rat model of *Neisseria meningitidis* meningitis was established.
- Intracisternal administration of heat-killed meningococci was used to induce meningitis.
- The MMP inhibitor batimastat (BB-94) was administered at different time points.
- Blood-brain barrier (BBB) permeability, intracranial pressure, and CSF white blood cell counts were assessed.
Main Results:
- Elevated concentrations of MMP-9 and TIMP-1 were detected in the CSF of bacterial meningitis patients compared to controls.
- Meningococcal meningitis in rats led to BBB disruption, increased intracranial pressure, and CSF pleocytosis.
- MMP-9 activity was observed in the CSF of infected rats.
- Batimastat treatment significantly reduced BBB disruption and intracranial pressure.
- Batimastat did not significantly reduce CSF white blood cell counts.
Conclusions:
- Matrix metalloproteinases (MMPs), particularly MMP-9, are involved in the breakdown of the blood-brain barrier during experimental bacterial meningitis.
- TIMP-1 levels are also elevated in bacterial meningitis patients, suggesting a role in regulating MMP activity.
- MMP inhibition shows therapeutic potential in mitigating key pathological features of meningitis, such as BBB disruption and increased intracranial pressure.
- Further research is warranted to explore MMPs as therapeutic targets for bacterial meningitis.