Pharmacologic interference with NF-κB activation attenuates central nervous system complications in experimental pneumococcal meningitis

Abstract

This study assessed the effects of 2 different inhibitors of NF-κB 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 IκB proteolysis, and BAY 11-7085, which inhibits IκB phosphorylation. Pneumococcal meningitis was associated with an increase in NF-κB 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 CO2 reactivity and auto-regulation. Thus, pharmacologic interference with NF-κB activation might be a possible target for adjunctive therapy in bacterial meningitis.