Oxidative Brain Damage by Peroxynitrite in Bacterial Meningitis: A Target for Adjunctive Therapy ?

The host response contributes greatly to the development of intracranial complications of acute bacterial meningitis. During recent decades, various host factors have been identified as potential targets for the adjunctive therapy of meningitis. Among these, radicals and oxidants are of great importance. Many of the detrimental effects of nitric oxide and superoxide seem to be mediated by their reaction product peroxynitrite. Peroxynitrite can be cytotoxic by several mechanisms, e.g., tyrosine nitration, initiation of lipid peroxidation, inhibition of mitochondrial respiration, induction of DNA strand breaks and activation of poly(ADP-ribose) polymerase, and increased production, release, or activation of proinflammatory cytokines, prostaglandins, or matrix metalloproteinases. An increase of tyrosine nitration was observed in the brain of experimental animals and humans with bacterial meningitis. In particular, cerebral blood vessels are affected by tyrosine nitration and lipid peroxidation during meningitis, suggesting that peroxynitrite may contribute to the development of cerebrovascular complications and blood-brain barrier disruption. Increased CSF nitrotyrosine concentrations were associated with an adverse outcome and patients with low serum concentrations of the natural peroxynitrite scavenger uric acid developed meningitis-associated intracranial complications more frequently. During experimental bacterial meningitis, treatment with the natural peroxynitrite scavenger uric acid was shown to reduce pathophysiological changes, such as blood-brain barrier disruption and increased intracranial pressure. These data suggest that peroxynitrite is an interesting target for the adjunctive therapy of bacterial meningitis.