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 PARP1 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-1β, -6, and tumor necrosis factor-α 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, PARP1-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.