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

Uwe Koedel1, Frank Winkler, Barbara Angele

  • 1Department of Neurology, Klinikum Grosshadern, Munich, Germany.

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
|January 25, 2002
PubMed

Insights

Poly(adenosine diphosphate-ribose) polymerase (PARP) activation contributes to brain injury in experimental pneumococcal meningitis. Inhibiting PARP protects against central nervous system complications and reduces inflammation, suggesting PARP inhibitors as potential therapies.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Pneumococcal meningitis can cause severe central nervous system (CNS) complications.
  • The role of poly(adenosine diphosphate-ribose) polymerase (PARP) activation in meningitis pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the role of PARP activation in experimental pneumococcal meningitis.
  • To evaluate the therapeutic potential of PARP inhibition.

Main Methods:

  • Utilized PARP 1 gene-deficient mice and wild-type mice infected with Streptococcus pneumoniae.
  • Administered the PARP inhibitor 3-aminobenzamide.
  • Assessed CNS complications, including blood-brain barrier integrity and intracranial pressure.
  • Measured inflammatory markers (cytokines, leukocytes) in cerebrospinal fluid and brain tissue.
  • Examined PARP activation and nicotinamide adenine dinucleotide levels in endothelial cells exposed to pneumococci.

Main Results:

  • PARP 1 deficiency protected mice from meningitis-associated CNS complications and inflammation.
  • PARP inhibition with 3-aminobenzamide conferred similar protection, reducing inflammation and improving clinical outcomes.
  • Pneumococcal challenge induced PARP activation and endothelial cell death, which was attenuated by 3-aminobenzamide.
  • PARP activation correlated with reduced cellular nicotinamide adenine dinucleotide levels and increased cytotoxicity.

Conclusions:

  • PARP activation plays a critical role in the pathogenesis of pneumococcal meningitis and associated CNS injury.
  • PARP inhibition demonstrates therapeutic potential for treating bacterial meningitis.
  • Targeting PARP activation may mitigate pneumococci-induced endothelial damage.

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