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Role of peroxynitrite as a mediator of pathophysiological alterations in experimental pneumococcal meningitis
S Kastenbauer1, U Koedel, H W Pfister
1Department of Neurology, Grosshadern Clinic, Ludwig-Maximilians-University, 81377 Munich, Germany.
Abstract:
This study investigated the role of peroxynitrite in an adult rat model of pneumococcal meningitis. Immunohistochemically, nitrotyrosine residues, as a marker for peroxynitrite formation, were detected perivascularly and in proximity to inflammatory cells in the subarachnoid space. Nitrotyrosine immunoreactivity was colocalized with blood-brain barrier breaching, which was visualized by fluorescence microscopy after intravenous application of Evans blue. Treatment of infected rats with uric acid (300 mg/kg intraperitoneally), a scavenger of peroxynitrite, significantly attenuated intracranial pressure, cerebrospinal fluid white blood cell count, and blood-brain barrier leakage, as indicated by Evans blue concentration in the cerebrospinal fluid (21.6+/-9.3 mm Hg, 5776+/-1790 cells/microL, 9.7+/-6.4 microgram/mL in infected, untreated rats vs. 7.2+/-1.6 mm Hg, 2004+/-904 cells/microL, 1.1+/-1.0 microgram/mL infected, uric acid-treated rats, mean+/-SD, P<.05). These data suggest that peroxynitrite plays a central role in mediating pathophysiological alterations during bacterial meningitis.
Insights
Peroxynitrite contributes to brain damage in pneumococcal meningitis. Uric acid, a peroxynitrite scavenger, reduced intracranial pressure, inflammation, and blood-brain barrier leakage in rats.
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Bacterial meningitis is a severe central nervous system infection.
- Peroxynitrite is a reactive nitrogen species implicated in inflammatory processes.
Purpose of the Study:
- To investigate the role of peroxynitrite in a rat model of pneumococcal meningitis.
- To evaluate the therapeutic potential of uric acid as a peroxynitrite scavenger.
Main Methods:
- Immunohistochemistry to detect nitrotyrosine (peroxynitrite marker).
- Evans blue staining to assess blood-brain barrier permeability.
- Measurement of intracranial pressure and cerebrospinal fluid white blood cell count.
Main Results:
- Nitrotyrosine deposition was observed in the subarachnoid space, colocalizing with blood-brain barrier disruption.
- Uric acid treatment significantly reduced intracranial pressure (P<.05).
- Uric acid significantly decreased cerebrospinal fluid white blood cell count and blood-brain barrier leakage (P<.05).
Conclusions:
- Peroxynitrite plays a critical role in the pathophysiology of pneumococcal meningitis.
- Scavenging peroxynitrite with uric acid demonstrates therapeutic potential in reducing meningitis-induced damage.