Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis.
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.
Leib
S L
SL
Institute for Infectious Diseases, University of Bern, Berne, Switzerland. stephen.leib@ifik.unibe.ch
Clements
J M
JM
Lindberg
R L
RL
Heimgartner
C
C
Loeffler
J M
JM
Pfister
L A
LA
Täuber
M G
MG
Leppert
D
D
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001593:Benzyl Compounds; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D015971:Gene Expression Regulation, Enzymologic; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010431:Pentoxifylline / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid
C101468:BB 1101; D001593:Benzyl Compounds; D017931:DNA Primers; D004338:Drug Combinations; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; D010431:Pentoxifylline