PREVENTION OF PERINATAL HYPOXIC-ISCHEMIC BRAIN DAMAGE

预防围产期缺氧缺血性脑损伤

基本信息

批准号：
2267835
负责人：
CHARLES PALMER
金额：
$ 9.66万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-04-01 至 1997-03-31
项目状态：
已结题

项目摘要

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.

本研究计划的总体目标是阐明氧自由基和中性粒细胞产生的机制导致围产期缺氧缺血性脑损伤。具体目标包括：1）确定羟基自由基发生的时间过程和程度已形成； 2) 确定中性粒细胞积累的程度导致围产期缺氧缺血性脑损伤； 3）探索别嘌呤醇和去铁胺的神经保护机制； 4）确定氧化损伤如何以及何时损害微血管功能。到为了实现这些目标，我们将使用既定的焦点模型产后7天大鼠缺氧缺血性脑损伤单侧颈总动脉闭塞并暴露于 8% 氧。我们将确定：1）别嘌呤醇的神经保护能力与其代谢物作为救援疗法； 2) 去铁胺作用部位使用羟基乙基淀粉缀合物； 3）自由基和中性粒细胞如何导致血脑屏障破坏、脑水肿、毛细血管闭塞和脑血流量； 3）时间进程和范围产生羟基自由基并导致缺氧缺血脑损伤，以便最好地……； 4) 确定治疗窗 “救援”（缺氧缺血后）治疗； 5) 确定程度中性粒细胞减少症和去铁胺和别嘌呤醇的“救援”治疗防止羟基自由基的形成； 6) 用于“拯救”别嘌呤醇和去铁胺可改善脑能量代谢物水平并预防脂质过氧化； 7) 确定黄嘌呤氧化酶对围产期缺氧缺血性脑损伤。分析程序将包括：1）通过测定脑水来评估脑损伤内容，以及神经病理学改变（肉眼可见的和微观的）产后30天； 2）脑组织提取物的生化分析用于脑能量代谢物、药代动力学和脂质氢过氧化物； 3) 通过测量特定产物来评估自由基的形成水杨酸羟基化； 4）大脑、血液中的黄嘌呤氧化酶活性心; 5) 血脑屏障通透性、毛细血管闭塞情况局部脑血流量。拟议研究的结果将为制定合理有效的治疗方法提供依据持续性脑损伤人类婴儿的管理方案围产期缺氧缺血。