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.
|
Authors | Uwe Koedel, Frank Winkler, Barbara Angele, Adriano Fontana, Hans-Walter Pfister |
Journal | Journal 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 |
PMID | 11807392
(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
|