MECHANISMS AND PREVENTION OF HEMOGLOBIN NEUROTOXICITY

血红蛋白神经毒性的机制和预防

• 批准号: 6183851
• 负责人: Samuel Scott Panter
• 金额: $ 24.27万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183851
• 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

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：（改编自研究者摘要） 该建议认为血红蛋白具有细胞毒性， 由原始缺血发作产生的细胞损伤。这一贡献 血红蛋白对神经损伤的影响可以通过用 抗氧化剂、螯合剂、血红蛋白结合蛋白触珠蛋白或试剂 堵塞屏障，阻止血红蛋白进入这项建议 将集中于大鼠局灶性缺血和再灌注模型， 被证明能破坏血脑屏障为了尝试模拟 在临床情况下，将输注无基质或纯化的人血红蛋白 在局灶性脑缺血后再灌注开始时， 缺血这一过程导致血红蛋白直接沉积到 通过破坏的血脑屏障进入脑缺血区。增加剂量的 将给予血红蛋白以评估行为障碍， 生存能力在中风后的不同时间间隔， 评估梗死面积、脑水肿和脑组织破坏程度。 血脑屏障神经元变性将通过常规检查评估。 组织学和荧光显微镜使用荧光玉。最后，动物将 用抗氧化剂（多硝基-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，或已被证明在物理上 堵住血脑屏障破裂的漏洞这些研究将描述 血红蛋白依赖性的神经损伤后开放的 血脑屏障，并将测试几种治疗候选人， 用于CABG手术的临床环境。