Neonatal bacterial meningitis leads to severe brain injury in many affected children. The goal of this research is to elucidate the mechanisms of brain injury. Several lines of evidence indicate that meningitis may involve the generation of reactie oxygen intermediates (ROI) and lead to oxidative injury to the brain. A critical role for ROI in meningitis is supported by findings that a scavenger of ROI (alpha-phenyl-tert-butyl-nitrone, PBN) dramatically protected infant rats with experimental neonatal meningitis from developing neuronal injury and was protective in primary co-cultures of neurons and glia stimulated with bacterial products and excitatory amino acids.
In Specific Aim 1, the principal investigator will analyze the generation of ROI in primary cultures of neurons, astrocyotes, or microglia in vitro, after stimulation by fragmented cell walls of group B streptococci, cytokines IL-1 and TNF-alpha, ischemia, or excitatory amino acids.
In Specific Aim 2, he will confirm the findings of Specific Aim 1 in his infant rat model by identifying production of ROI in the CNS and the effects of ROI scavengers in limiting ROI production, cytotoxicity, and neuronal injury.
In Specific Aim 3, he will attempt to dissect the mechanisms by which ROI produce neuroonal injury, again in the infant rat model, by quantitating the effects of ROI scavengers on meningeal inflammation, cerebral ischemia, nitrotyrosine formation, and glial cell activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS034028-03S1
Application #
6073781
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Spinella, Giovanna M
Project Start
1996-12-23
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Loeffler, J M; Ringer, R; Hablutzel, M et al. (2001) The free radical scavenger alpha-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J Infect Dis 183:247-252
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Christen, S; Bifrare, Y D; Siegenthaler, C et al. (2001) Marked elevation in cortical urate and xanthine oxidoreductase activity in experimental bacterial meningitis. Brain Res 900:244-51
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Pfister, L A; Tureen, J H; Shaw, S et al. (2000) Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Ann Neurol 47:329-35
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Auer, M; Pfister, L A; Leppert, D et al. (2000) Effects of clinically used antioxidants in experimental pneumococcal meningitis. J Infect Dis 182:347-50
Leib, S L; Tauber, M G (1999) Pathogenesis of bacterial meningitis. Infect Dis Clin North Am 13:527-48, v-vi

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