MECHANISMS AND PREVENTION OF HEMOGLOBIN NEUROTOXICITY

描述：(改编自调查人员摘要)的中心假设 这项建议认为，血红蛋白具有细胞毒性，并且会显著恶化。 最初的缺血发作所造成的细胞损伤。这一贡献 血红蛋白对神经损伤的保护作用可通过预先给予 抗氧化剂、螯合剂、血红蛋白结合蛋白或试剂 这将堵塞屏障，阻止血红蛋白进入。这项建议 将重点放在大鼠局灶性缺血和再灌注模型上 证明可以破坏血脑屏障。要尝试对 临床情况，无基质或提纯的人血红蛋白将被输注 大鼠局灶性脑缺血后再灌流开始时的血管系统 缺血症。这一过程导致血红蛋白直接沉积到 大脑的缺血区通过被破坏的血脑屏障。不断增加的剂量 将注射血红蛋白来评估行为障碍和 生存能力。在中风后的不同时间间隔，大脑将被 评估梗塞范围、脑水肿和大脑中动脉受阻程度 血脑屏障。神经元变性将通过常规方法进行评估 组织学和荧光显微镜采用氟玉。最后，动物们会 用抗氧化剂(多氮氧基白蛋白)、铁络合剂(a 淀粉去铁胺结合物)，正常的血红蛋白结合蛋白 结合珠蛋白，或五星类的一个亚组分，已被物理证明 堵住被破坏的血脑屏障的漏洞。这些研究将描绘出 血红蛋白依赖在心脏开放术后神经损伤中的作用 并将测试几种可能的治疗候选药物 用于冠脉搭桥术的临床环境。

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.