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.
Showing the most recent 10 out of 14 publications
