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 i nclude: 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.
| Viswanath, M; Palmer, C; Roberts, R L (2000) Reduction of hypoxic-ischemic brain swelling in the neonatal rat with PAF antagonist WEB 2170: lack of long-term protection. Pediatr Res 48:109-13 |
| Palmer, C; Menzies, S L; Roberts, R L et al. (1999) Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J Neurosci Res 56:60-71 |
| Hudome, S; Palmer, C; Roberts, R L et al. (1997) The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 41:607-16 |
| Connor, J R; Pavlick, G; Karli, D et al. (1995) A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol 355:111-23 |
| Palmer, C; Roberts, R L; Bero, C (1994) Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke 25:1039-45 |
| Palmer, C; Towfighi, J; Roberts, R L et al. (1993) Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res 33:405-11 |
