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Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase.

Abstract
The present study assessed the role of PARP [poly(adenosine diphosphate-ribose) polymerase] activation in experimental pneumococcal meningitis. Mice with a targeted disruption of the PARP 1 gene were protected against meningitis-associated central nervous system complications including blood-brain barrier breaching and increase in intracranial pressure. This beneficial effect was paralleled by a significant reduction in meningeal inflammation, as evidenced by significantly lower cerebrospinal fluid leukocyte counts and interleukin-1beta, -6, and tumor necrosis factor-alpha concentrations in the brain (compared with infected wild-type mice). The reduction in inflammation and central nervous system complications was associated with an improved clinical status of infected, PARP 1-deficient mice. A similar protective effect was achieved by PARP inhibition using 3-aminobenzamide, the pharmacologic efficacy of which was confirmed by a marked attenuation of meningitis-induced poly(ADP)ribose formation. When the rat brain-derived endothelial cell line GP8.3 was cocultured with macrophages, exposure to pneumococci induced endothelial cell death and was paralleled by PARP activation and a reduction in the oxidized form of cellular nicotinamide adenine dinucleotide content. Treatment with 3-aminobenzamide significantly attenuated cellular nicotinamide adenine dinucleotide depletion and pneumococci-induced cytotoxicity. Thus, PARP activation seems to play a crucial role in the development of meningitis-associated central nervous system complications and pneumococci-induced endothelial injury. Inhibitors of PARP activation could provide a potential therapy of acute bacterial meningitis.
AuthorsUwe Koedel, Frank Winkler, Barbara Angele, Adriano Fontana, Hans-Walter Pfister
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 22 Issue 1 Pg. 39-49 (Jan 2002) ISSN: 0271-678X [Print] United States
PMID11807392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • Enzyme Inhibitors
  • Membrane Proteins
  • Occludin
  • Ocln protein, mouse
  • Ocln protein, rat
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • 3-aminobenzamide
  • Poly(ADP-ribose) Polymerases
Topics
  • Animals
  • Benzamides (pharmacology)
  • Brain (pathology, physiopathology)
  • Brain Chemistry
  • Cell Line
  • Central Nervous System Diseases (etiology, immunology, physiopathology)
  • Disease Models, Animal
  • Endothelium, Vascular (drug effects, metabolism, pathology)
  • Enzyme Activation
  • Enzyme Inhibitors (pharmacology)
  • In Situ Nick-End Labeling
  • Macrophages (metabolism)
  • Male
  • Membrane Proteins (metabolism)
  • Meningitis, Pneumococcal (complications, enzymology, immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Occludin
  • Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases (genetics, metabolism)
  • Rats

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