Perinatal hypoxic-ischemic encephalopathy is a major cause of chronic neurologic disorders in children and adults. Developing motor systems in the brain are particularly vulnerable to perinatal injury. Unilateral carotid artery ligation and subsequent exposure to 8% oxygen in 7 day old rats leads to reproducible ischemic neuronal damage limited to forebrain ipsilateral to ligation. This is a useful small animal model for study of perinatal brain injury. Using this well characterized model, the proposal will focus on examination of the role of the excitatory neurotransmitter glutamate in the pathogenesis of ischemic neuronal injury and on identification of features of ischemic injury which are relevant in the immature brain. Hypoxia-ischemia induced alterations in the distribution and pharmacology of post-synaptic glutamate receptors will be analyzed using in vitro 3H-glutamate autoradiography. Animals treated with the neuroprotective glutamate antagonist MK -801 will be used to dissect -the relationship between receptor changes and evolution of neuronal injury. Biochemical factors that regulate high affinity glutamate uptake(HAGU) in the developing nervous system will be examined and the impact of hypoxia-ischemia on HAGU will be assessed in synaptosomes derived from lesioned brain. Chemical modulation of striatal glutamate release in immature brain and the effects of hypoxia- ischemia on glutamate release will be studied with in vivo microdialysis. This work will provide a better understanding of the neurobiology of perinatal hypoxic-ischemic brain injury and may provide a basis for development of more specific and effective therapeutic interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurology B Subcommittee 2 (NEUB)
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Ivacko, J A; Sun, R; Silverstein, F S (1996) Hypoxic-ischemic brain injury induces an acute microglial reaction in perinatal rats. Pediatr Res 39:39-47
Szaflarski, J; Burtrum, D; Silverstein, F S (1995) Cerebral hypoxia-ischemia stimulates cytokine gene expression in perinatal rats. Stroke 26:1093-100
Burtrum, D; Silverstein, F S (1994) Hypoxic-ischemic brain injury stimulates glial fibrillary acidic protein mRNA and protein expression in neonatal rats. Exp Neurol 126:112-8
Maragos, W F; Silverstein, F S (1994) Resistance to nitroprusside neurotoxicity in perinatal rat brain. Neurosci Lett 172:80-4
Nelson, C; Silverstein, F S (1994) Acute disruption of cytochrome oxidase activity in brain in a perinatal rat stroke model. Pediatr Res 36:12-9
Barks, J D; Silverstein, F S (1994) The glutamate uptake inhibitor L-trans-2,4-pyrrolidine dicarboxylate is neurotoxic in neonatal rat brain. Mol Chem Neuropathol 23:201-15
Burtrum, D; Silverstein, F S (1993) Excitotoxic injury stimulates glial fibrillary acidic protein mRNA expression in perinatal rat brain. Exp Neurol 121:127-32
Chen, C K; Silverstein, F S; Johnston, M V (1992) N-methyl-D-aspartate-mediated injury enhances quisqualic acid-stimulated phosphoinositide turnover in perinatal rats. J Neurochem 59:963-71
Barks, J D; Silverstein, F S (1992) Excitatory amino acids contribute to the pathogenesis of perinatal hypoxic-ischemic brain injury. Brain Pathol 2:235-43
Silverstein, F S; Naik, B; Simpson, J (1991) Hypoxia-ischemia stimulates hippocampal glutamate efflux in perinatal rat brain: an in vivo microdialysis study. Pediatr Res 30:587-90

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