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MECHANISMS AND PREVENTION OF HEMOGLOBIN NEUROTOXICITY

血红蛋白神经毒性的机制和预防

基本信息

批准号：
6526867
负责人：
Samuel Scott Panter
金额：
$ 25.68万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-01 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6526867
关键词：
behavior test blood brain barrier cerebral ischemia /hypoxia chelation therapy fluorescence microscopy free radical scavengers haptoglobins hemoglobin hemolysis histology laboratory rat neural degeneration neuroprotectants neurotoxins nonhuman therapy evaluation oxidative stress reperfusion

项目摘要

DESCRIPTION: (Adapted from investigator's abstract) The central hypothesis of this proposal is that hemoglobin is cytotoxic and will significantly worsen cellular injury produced by the original ischemic episode. This contribution of hemoglobin to neurological injury can be reduced by pretreatment with antioxidants, chelators, the hemoglobin binding protein haptoglobin, or agents that will plug the barrier, blocking the entry of hemoglobin. This proposal will focus on a rat model of focal ischemia and reperfusion that has been demonstrated to disrupt the blood-brain barrier. To attempt to model the clinical situation, stroma-free or purified human hemoglobin will be infused into the vasculature of rats at the start of reperfusion following focal ischemia. This procedure results in the direct deposition of hemoglobin into the ischemic area of the brain through the disrupted BBB. Increasing doses of hemoglobin will be administered to assess behavioral impairment and survivability. At different time intervals following stroke, the brains will be evaluated for infarct size, cerebral edema, and the degree of disruption of the blood-brain barrier. Neuronal degeneration will be assessed by conventional histology and fluorescence microscopy using fluoro-jade. Finally, animals will be pretreated with an antioxidant (polynitroxyl-albumin), an iron chelator (a starch deferoxamine conjugate), the normal hemoglobin-binding protein haptoglobin, or a subfraction of pentastarch that has been shown to physically plug the holes of a disrupted blood-brain barrier. These studies will delineate a hemoglobin-dependent contribution to neural injury following opening of the blood-brain barrier and will test several therapeutic candidates that could be used in the clinical setting of CABG surgery.

描述：（改编自研究者的摘要）中心假设这个提议是血红蛋白具有细胞毒性并且会显着恶化最初的缺血发作产生的细胞损伤。这一贡献通过预处理可以减少血红蛋白对神经的损伤抗氧化剂、螯合剂、血红蛋白结合蛋白触珠蛋白或药剂这会堵塞屏障，阻止血红蛋白的进入。这个提议将重点研究局灶性缺血和再灌注的大鼠模型被证明会破坏血脑屏障。尝试建模临床情况，将输注无基质或纯化的人血红蛋白在局部再灌注开始时进入大鼠的脉管系统缺血。该过程导致血红蛋白直接沉积到通过破坏的血脑屏障到达大脑缺血区域。增加剂量将使用血红蛋白来评估行为障碍和生存能力。中风后的不同时间间隔，大脑会评估梗塞面积、脑水肿以及脑梗死的破坏程度血脑屏障。神经元变性将通过常规评估使用氟玉进行组织学和荧光显微镜检查。最后，动物会用抗氧化剂（聚硝酰基白蛋白）、铁螯合剂（a 淀粉去铁胺结合物），正常血红蛋白结合蛋白触珠蛋白，或五淀粉的一种亚组分，已被证明具有物理作用堵塞受损的血脑屏障的漏洞。这些研究将描绘血红蛋白依赖性对神经损伤的贡献血脑屏障，并将测试几种可能的治疗候选药物用于CABG手术的临床环境。