Differential expression of nitric oxide synthases in bacterial meningitis: Role of the inducible isoform for blood-brain barrier breakdown

Abstract

The aim of the study was to determine the differential expression of nitric oxide (NO) synthase (NOS) isoforms and the pathophysiologic relevance of inducible NOS (iNOS) in experimental pneumococcal meningitis. By use of reverse transcription-polymerase chain reaction analysis, immunohistochemistry, and Western blotting, increased brain mRNA and increased protein levels of endothelial NOS (eNOS) and iNOS were detected 24 h after intracisternal pneumococcal inoculation. In iNOS-deficient mice, disruption of the blood-brain barrier (BBB) was significantly reduced, compared with that in wild-type mice. This beneficial effect of iNOS deficiency was associated with a lack of nitrotyrosine immunoreactivity. Furthermore, brain protein levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and brain mRNA levels of macrophage inflammatory protein (MIP)-1α and MIP-2 were significantly reduced in infected animals lacking iNOS. These findings suggest that (1) not only iNOS but also eNOS is up-regulated in the acute phase of experimental bacterial meningitis, and (2) iNOS-derived NO contributes to peroxynitrite formation and BBB breaching in this disease.