Intranasal Deferoxamine to Precondition Against Stroke

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明显的神经功能障碍，包括中风和认知功能障碍。事实上，高危人群中的患者脑部不良结局的发生率超过16%。对这一提议的研究针对的是一种模型，该模型利用一种技术，通过对大脑进行预调节，使其对缺血侮辱更具抵抗力，从而减少围手术期的神经问题。我们将尝试使用大脑中动脉阻塞(MCAO)的大鼠模型来实现这一目标，并尝试使用一种独特的药物输送系统-鼻腔给药来进行预适应。我们选择使用的药物-去铁胺(DFO)-已经在许多实验系统中被证明是预适应的，从细胞培养到新生动物再到成年动物。在这些研究中，DFO的给药提供了对缺血的保护；然而，DFO的非肠道给药是有问题的，因为它的半衰期很短，而且有副作用。这一方案的实验将利用大鼠鼻内注射DFO。首先，用微量的~(59)Fe铁标记的DFO放射性核素记录鼻腔DELI，定性和定量测定脑内DFO的量。其次，将确定诱导HIF1α的剂量-反应关系及其随时间的耐受性。第三，在最大限度地诱导HIF-1α的时间点，将进行MCAO，并评估神经学结果和脑梗塞范围。我们的初步研究表明，三个剂量的DFO滴鼻，相隔三个小时，显著上调48小时后大脑中HIF-1α的浓度。当在这个时间点进行MCAO时，观察到梗塞面积减少了65%。这些研究可能会产生可以转化为临床的数据，并最终为接受手术的患者提供神经保护，这些手术可能会使他们面临神经损伤的风险，比如冠状动脉搭桥手术。

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.