Inducible nitric oxide synthase mediates hippocampal caspase-3 activation in pneumococcal meningitis

Abstract

Brain damage in bacterial meningitis is still a major problem. More knowledge about the triggers and mechanisms of neuronal damage in bacterial meningitis is needed to improve outcome in bacterial meningitis. The most common bacterial meningitis pathogen--Streptococcus pneumoniae--causes caspase activation and neuronal apoptosis in the hippocampus via its toxins and extensive inflammatory potential. Nitric oxide (NO)--produced by inducible nitric oxide synthase (iNOS)--is a major inflammatory mediator clearly upregulated in the cerebrospinal fluid during pneumococcal meningitis. However, its effects in bacterial meningitis are still controversial. This article demonstrates that genetic inactivation of iNOS results in a marked reduction of caspase-3-mediated neuronal damage in experimental murine pneumococcal meningitis. Protection of hippocampal neurons in iNOS knockout mice was not due to differences in intrathecal growth of S. pneumoniae and must therefore be attributed to differences of host inflammatory mediators. This indicates that NO plays an important role in hippocampal caspase-3 activation during pneumococcal meningitis.