Project: Research project

Project Details


The overall objective of this research proposal is to elucidate the
mechanisms whereby the production of oxygen free radicals and neutrophils
contribute to perinatal hypoxic-ischemic brain damage. Specific aims
include: 1) to ascertain the time course and extent that hydroxyl radicals
are formed; 2) to determine to what extent neutrophils accumulate and
contribute to perinatal hypoxic-ischemic brain damage; 3) to explore the
neuroprotective mechanisms of allopurinol and deferoxamine; 4) to determine
how and when oxidative injury impairs microvascular function. To
accomplish these goals, we will use an established model of focal
hypoxic-ischemic brain injury in 7-day postnatal rats which are subjected
to unilateral common carotid artery occlusion combined with exposure to 8%
oxygen. We will determine: 1) the neuroprotective abilities of allopurinol
vs its metabolites as rescue therapy; 2) the site of deferoxamine action by
using hydroxyethlystarch conjugates; 3) how free radicals and neutrophils
contribute to disruption in the blood brain barrier, cerebral edema,
capillary occlusion and cerebral blood flow; 3) the time course and extent
to which hydroxyl radicals are generated and contribute to hypoxic ischemic
brain damage so as to best..; 4) determine the therapeutic window for
"rescue" (post hypoxia-ischemia) treatment; 5) determine the extent that
neutropenia and "rescue" treatment with deferoxamine and allopurinol
prevent hydroxyl radical formation and; 6) for "rescue" allopurinol and
deferoxamine to improve the levels of brain energy metabolites and prevent
lipid peroxidation; 7) determine the contribution of xanthine oxidase to
hypoxic-ischemic perinatal brain injury. Analytical procedures will
include: 1) assessment of brain injury from determinations of brain water
content, as well as neuropathologic alterations (gross and microscopic) at
30 days of postnatal age; 2) biochemical analysis of brain tissue extracts
for cerebral energy metabolites, pharmacokinetics and lipid hydroperoxides;
3) assessment of free radical formation by measuring specific products of
salicylate hydroxylation; 4) xanthine oxidase activity in brain, blood and
heart; 5) blood brain barrier permiability, capillary occlusion and
regional cerebral blood flow. Results of the proposed research will
provide a basis for the development of rational and effective treatment
protocols for the management of human -infants who have sustained cerebral
hypoxia-ischemia-during the perinatal-period.
Effective start/end date4/1/923/31/93


  • National Institute of Neurological Disorders and Stroke

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