This study assessed the effects of 2 different inhibitors of NF-kappaB activation on central nervous system complications and clinical symptoms in an advanced stage of experimental pneumococcal meningitis: the calpain inhibitor I N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), which interferes with IkappaB proteolysis, and BAY 11-7085, which inhibits IkappaB phosphorylation. Pneumococcal meningitis was associated with an increase in NF-kappaB activity, as determined by immunohistochemistry and Western blot analysis of rat brains 24 h after infection. Treatment with ALLN or BAY 11-7085 improved the clinical scores of infected rats, compared with those of untreated infected rats. This beneficial effect was parallelled by a significant reduction of the increase in intracranial pressure, blood-brain barrier permeability (as measured by the Evans blue-extravasation technique), cerebrospinal fluid (CSF) pleocytosis, CSF interleukin-6 levels, and impairment of cerebrovascular CO(2) reactivity and autoregulation. Thus, pharmacologic interference with NF-kappaB activation might be a possible target for adjunctive therapy in bacterial meningitis.

Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) have been suggested to play an important role in inflammatory diseases. Increased levels of tPA, uPA, uPA receptor (uPAR), and their inhibitor, plasminogen activator inhibitor (PAI)-1, have been found in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Here, we show that expression of tPA, uPA, uPAR, PAI-1, and PAI-2 is up-regulated during experimental pneumococcal meningitis. In uPAR-deficient mice, CSF pleocytosis was significantly attenuated 24 h after infection, compared with that in infected wild-type (wt) mice. Lack of uPAR did not influence blood-brain barrier permeability, intracranial pressure, expression of chemokines (keratinocyte-derived cytokine and macrophage inflammatory protein-2), bacterial killing, or clinical outcome. No differences in pathophysiological alterations were observed in tPA-deficient mice, compared with those in infected wt mice. These results indicate that uPAR participates in the recruitment of leukocytes to the CSF space during pneumoccal meningitis.