Document Detail


Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis.
MedLine Citation:
PMID:  10639424     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) were significantly (P < 0.04) upregulated, compared to the beta-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-alpha in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0. 001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P < 0.02) and TNF-alpha (P < 0.02) levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.
Authors:
S L Leib; D Leppert; J Clements; M G Täuber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Infection and immunity     Volume:  68     ISSN:  0019-9567     ISO Abbreviation:  Infect. Immun.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-02-10     Completed Date:  2000-02-10     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  615-20     Citation Subset:  IM    
Affiliation:
Institute for Medical Microbiology, University of Berne, Berne, Switzerland. sleib@imm.unibe.ch
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain / pathology*
Matrix Metalloproteinase 9 / cerebrospinal fluid
Matrix Metalloproteinases / antagonists & inhibitors,  genetics,  physiology*
Meningitis, Pneumococcal / pathology*
RNA, Messenger / analysis
Rats
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha / cerebrospinal fluid,  genetics
Grant Support
ID/Acronym/Agency:
NS32553/NS/NINDS NIH HHS; NS34028/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections

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