Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis.
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.
Department of Neurology, Ludwig-Maximilians-University of Munich, Klinikum Brosshadern, Germany.
R
R
Paul
S
S
Lorenzl
U
U
Koedel
B
B
Sporer
U
U
Vogel
M
M
Frosch
H W
HW
Pfister
D000328:Adult; D000368:Aged; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002555:Cerebrospinal Fluid / Q000166:cytology; D017364:Collagenases / Q000134:cerebrospinal fluid / Q000502:physiology*; D005260:Female; D006801:Humans; D007427:Intracranial Pressure / Q000187:drug effects / Q000502:physiology; D007958:Leukocyte Count; D008297:Male; D020780:Matrix Metalloproteinase 9; D008585:Meningitis, Meningococcal / Q000201:enzymology / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008875:Middle Aged; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000134:cerebrospinal fluid
D013876:Thiophenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9