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Inhibition of the Kynurenine-NAD+ Pathway Leads to Energy Failure and Exacerbates Apoptosis in Pneumococcal Meningitis

Pneumococcal meningitis causes neurological sequelae, including learning and memory deficits in up to half of the survivors. In both humans and in animal models of the disease, there is apoptotic cell death in the hippocampus, a brain region involved in learning and memory function. We previously demonstrated that in an infant rat model of pneumococcal meningitis, there is activation of the kynurenine(KYN) pathway in the hippocampus, and that there was a positive correlation between the concentration of 3-hydroxykynurenine and the extent of hippocampal apoptosis. To clarify the role of the KYN pathwayin the pathogenesis of hippocampal apoptosis in pneumococcal meningitis, we specifically inhibited 2 key enzymes of the KYN pathwayand assessed hippocampal apoptosis, KYN pathway metabolites, and nicotinamide adenine dinucleotide (NAD) concentrations by high-performance liquid chromatography. Pharmacological inhibition of kynurenine 3-hydroxylase and kynureninase led to decreased cellular NAD+ levels and increased apoptosis in the hippocampus. The cerebrospinalfluid levels of tumor necrosis factor and interleukin-1&agr; and -&bgr; werenotaffected. Our data suggest that activation of the KYN pathwayin pneumococcal meningitis is neuroprotective by compensating foran increased NAD+ demand caused by infection and inflammation;this mechanism may prevent energy failure and apoptosis in the hippocampus.