PREVENTION OF PERINATAL HYPOXIC-ISCHEMIC BRAIN DAMAGE

预防围产期缺氧缺血性脑损伤

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/2267835
• 关键词: allopurinol; artery occlusion; biochemistry; bioenergetics; blood brain barrier; body water; brain circulation; brain disorder chemotherapy; brain edema; brain injury; brain metabolism; capillary; cerebral ischemia /hypoxia; chronic brain damage; deferoxamine; developmental neurobiology; disease /disorder model; disease /disorder prevention /control; embryo /fetus chemotherapy; free radical oxygen; granulocytopenia; high performance liquid chromatography; hydroxyl radical; hypoxia neonatorum; laboratory rat; lipid peroxides; microcirculation; neuroprotectants; neutrophil; newborn animals; perinatal; pharmacokinetics; reperfusion; xanthine dehydrogenase

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.

该研究建议的总体目的是阐明 产生氧自由基和中性粒细胞的机制 有助于围产期缺氧 - 缺血性脑损伤。 具体目标 包括：1）确定羟基自由基的时间过程和程度 形成； 2）确定中性粒细胞在多大程度上积聚和 有助于围产期缺氧 - 缺血性脑损伤； 3）探索 别嘌醇和脱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 实现这些目标，我们将使用既定的焦点模型 7天后大鼠的缺氧缺血性脑损伤 单侧共同的颈动脉闭塞，并暴露于8％ 氧。 我们将确定：1）别嘌醇的神经保护能力 与其代谢物作为救援疗法； 2）通过 使用羟基淀粉结合物； 3）自由基和中性粒细胞如何 有助于血液脑屏障的干扰，大脑水肿， 毛细血管阻塞和脑血流动； 3）时间课程和范围 产生羟基自由基并导致缺氧性缺血 脑损伤，以至于最好。 4）确定治疗窗口 “救援”（缺氧 - 缺血后）治疗； 5）确定程度 中性粒细胞减少症和deferoxamine和别嘌醇的“救援”治疗 预防羟基自由基形成和； 6）用于“营救”别嘌醇和 脱氧胺以改善脑能量代谢物的水平并防止 脂质过氧化； 7）确定黄嘌呤氧化酶对 低氧 - 缺血性围产期脑损伤。 分析程序将 包括：1）通过确定脑水评估脑损伤 含量以及神经病理学改变（总和显微镜） 产后30天； 2）脑组织提取物的生化分析 用于大脑能代谢物，药代动力学和脂质氢过氧化物； 3）通过测量特定产物的自由基形成评估 水杨酸羟基化； 4）大脑，血液和 心; 5）血脑屏障的允许性，毛细管阻塞和 区域大脑血流。 拟议的研究结果将 为发展理性有效的治疗提供了基础 维持大脑的人类管理的协议 缺氧 - 缺血性围产期。