Inhibition of the kynurenine-NAD+ pathway leads to energy failure and exacerbates apoptosis in pneumococcal meningitis

Bellac, Caroline L.; Coimbra, Roney S.; Christen, Stephan; Leib, Stephen L. (2010). Inhibition of the kynurenine-NAD+ pathway leads to energy failure and exacerbates apoptosis in pneumococcal meningitis. Journal of neuropathology and experimental neurology, 69(11), pp. 1096-1104. Hagerstown, Md.: Lippincott Williams & Wilkins 10.1097/NEN.0b013e3181f7e7e9

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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 pathway in the pathogenesis of hippocampal apoptosis in pneumococcal meningitis, we specifically inhibited 2 key enzymes of the KYN pathway and 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 cerebrospinal fluid levels of tumor necrosis factor and interleukin-1? and -? were not affected. Our data suggest that activation of the KYN pathway in pneumococcal meningitis is neuroprotective by compensating for an increased NAD demand caused by infection and inflammation;this mechanism may prevent energy failure and apoptosis in the hippocampus.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases

UniBE Contributor:

Christen, Stephan and Leib, Stephen

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-3069

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:08

Last Modified:

24 Jul 2015 10:26

Publisher DOI:

10.1097/NEN.0b013e3181f7e7e9

PubMed ID:

20940631

Web of Science ID:

000283491800002

BORIS DOI:

10.7892/boris.639

URI:

https://boris.unibe.ch/id/eprint/639 (FactScience: 199911)

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