Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase.
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.
Koedel
Uwe
U
Department of Neurology, Klinikum Grosshadern, Munich, Germany.
Winkler
Frank
F
Angele
Barbara
B
Fontana
Adriano
A
Pfister
Hans-Walter
HW
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry; D002460:Cell Line; D002493:Central Nervous System Diseases / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008586:Meningitis, Pneumococcal / Q000150:complications* / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062793:Occludin; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D001549:Benzamides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases