Intranasal Deferoxamine to Precondition Against Stroke

鼻内去铁胺预防中风

• 批准号: 7009629
• 负责人: Samuel Scott Panter
• 金额: $ 18.63万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-24 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009629
• 关键词: autoradiography; cardiovascular disorder chemotherapy; cerebrovascular occlusions; coronary bypass; deferoxamine; disease /disorder model; dosage; hypoxia inducible factor 1; immunocytochemistry; inhalation drug administration; ischemic preconditioning; laboratory rat; model design /development; neuropharmacology; neuroprotectants; nonhuman therapy evaluation; stroke; western blottings

DESCRIPTION (provided by applicant): Coronary artery bypass graft (CABG) surgery is a procedure after which patients manifest significant neurological dysfunction, including stroke and cognitive impairment. In fact, patients in high-risk groups have an incidence of adverse cerebral outcome greater than 16%. The studies of this proposal are directed toward a model that utilizes a technique that may reduce perisurgical neurological problem by preconditioning the brain to be more resistant to ischemic insults. We will try to accomplish this goal using a rat model of middle cerebral artery occlusion (MCAO), and we will attempt to precondition using a unique drug delivery system-intranasal. The drug we have chosen to use-deferoxamine (DFO)-has been demonstrated to precondition in a number of experimental systems, from cell culture to neonatal animals to adult animals. The administration of DFO in these studies provided protection from ischemia; however, the parenteral administration of DFO is problematic because of its short half-life and side-effects. The experiments of this proposal will utilize intranasal deli very of DFO in rats. First, intranasal deli very will documented using DFO radio labeled with a small quantity of ferric 59Fe, and the amount of DFO in brain will be determined qualitatively and quantitatively. Second, a dose-response relationship for the induction of HIF1alpha and its endurance over time will be determined. Third, at the time point of maximal HIF-1 alpha induction, a MCAO will be performed and neurological outcome and infarct size will be assessed. Our preliminary studies indicate that three doses of intranasal DFO, three hours apart, significantly up-regulate the concentration of HIF-1alpha in brain 48 hours later. When a MCAO is performed at this time point, a 65% reduction in infarct size was observed. These studies may yield data that could be translated into the clinic and eventually provide neuroprotection to patients undergoing procedures that put them at risk for neurological injury, such as CABG surgery.

描述（由申请人提供）： 冠状动脉旁路移植术（CABG）是一种手术，患者在手术后表现出显著的神经功能障碍，包括中风和认知障碍。事实上，高危组患者不良脑预后的发生率大于16%。该建议的研究是针对一种模型，该模型利用了一种技术，该技术可以通过对大脑进行预处理以更好地抵抗缺血性损伤来减少围手术期神经问题。我们将尝试使用大鼠大脑中动脉闭塞（MCAO）模型来实现这一目标，并且我们将尝试使用独特的药物递送系统鼻内进行预处理。我们选择使用的药物-去铁胺（DFO）-已被证明可以在许多实验系统中进行预处理，从细胞培养到新生动物再到成年动物。在这些研究中，DFO的给药提供了缺血保护;然而，DFO的胃肠外给药是有问题的，因为它的半衰期短和副作用。本实验拟采用大鼠鼻内注射DFO的方法。首先，用少量铁离子59 Fe放射性标记DFO，观察其鼻内释放情况，并对脑内DFO含量进行定性和定量测定。其次，将确定HIF 1 α诱导的剂量-反应关系及其随时间的耐受性。第三，在最大HIF-1 α诱导的时间点，将进行MCAO，并评估神经学结果和梗死面积。我们的初步研究表明，三个剂量的DFO鼻内，间隔三小时，显着上调HIF-1 α在脑中的浓度48小时后。当在该时间点进行MCAO时，观察到梗死面积减少65%。这些研究可能产生的数据可以转化为临床，并最终为接受手术的患者提供神经保护，这些手术使他们面临神经损伤的风险，例如CABG手术。