NMR STUDIES OF HEMORRHAGIC TRANSFORMATION IN ISCHEMIA

描述：(逐字摘自申请人的摘要)治疗进展 使用溶栓剂的人类急性中风的发病率增加 对再灌流中出血转化(HT)的处理感兴趣 缺血性脑梗塞。临床试验表明，这种溶栓药物 Rt-PA可改善某些缺血性中风患者的预后，但 伴随着出现症状的高血压风险的增加。更高的利用率 因此，急性卒中的溶栓治疗将取决于临床医生的 识别有患高血压风险的患者的能力和技术 将此类风险降至最低。在这个项目中，我们将测试三个具体的目标和 假设。目的1建立大鼠大脑中动脉闭塞模型 缺血性卒中(MCAO)Ht模型的建立及缺血持续时间(1-2)的建立 小时)，在24小时内分别产生25%、50%和75%的高血压发病率 再灌流。我们推测，大脑中动脉阻塞后高血压的发展将取决于 从缺血开始到再灌流的时间。目标2A将是 急性血脑屏障(BBB)破坏与脑出血关系的研究 大鼠局灶性脑缺血模型大鼠缺血脑组织中羟色胺的演变 目标1)通过跟踪Gd-DTPA摄取建立了3-羟色胺的发病率 使用磁共振成像(MRI)。放射性标记化学品，14C标记 Gd-DTPA和55Fe标记的红细胞将用于验证MRI 放射自显影定量测量及血浆Gd-DTPA的建立 时间-浓度曲线。Aim 2A的假设是，HT的发生是由于 导致血脑屏障破坏的急性内皮损伤。增强后的磁共振成像 Gd-DTPA脑缺血组织可显示急性血脑屏障损伤 先于高血压的发展，并提供血脑屏障的定量估计 Gd-DTPA渗透性表面产品(PS产品)和分布空间 可能为高血压提供一个有用的危险指标。目标2B将调查 血压、脑灌注、脑血流量(CBF)和 心肌梗死面积与急性Gd-DTPA摄取和随后的HT的关系以验证这一假设 摄取Gd-DTPA和随后的HT的频率和程度将是 受组织的血流状态和较大、更严重的影响 缺血性脑梗塞。目标3将检查溶栓剂是否 Rt-PA增加大鼠甲状旁腺功能障碍的发生率和/或严重程度 MCAO模型。目标3的假设是，rt-PA将影响高血压的严重程度 出血，因此Gd-DTPA增强区域的大小和/或比率 在缺血和再灌注急性期摄取，但不会增加 羟色胺在大鼠大脑中动脉阻塞模型中的表达。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Advances in the treatment of acute stroke in humans using thrombolytic agents have prompted an increased interest in the management of hemorrhagic transformation (HT) in reperfused ischemic infarction. Clinical trials have shown that the thrombolytic drug rt-PA improves the outcome of certain patients with ischemic stroke, but is accompanied by an increased risk of symptomatic HT. Increased utilization of thrombolytic therapy in acute stroke, therefore, will depend on the clinician's ability to identify patients at risk of developing HT and techniques to minimize such risks. In this project, we will test three specific aims and hypotheses. Aim 1 will be to develop a rat middle cerebral artery occlusion (MCAO) model of Ht in ischemic stroke and establish ischemic durations (1-2 hours) that produce 25%, 50% and 75% HT incidence rates at 24 hours post reperfusion. We hypothesize that the development of HT after MCAO will depend on the time between the onset of ischemia and reperfusion. Aim 2A will be to study the relationship of acute blood brain barrier (BBB) disruption to evolving HT of ischemic brain tissue (produced using the rat MCAO model of HT with the 3 HT incidence rates established in Aim 1) by tracking Gd-DTPA uptake using magnetic resonance imaging (MRI). Radiolabeled chemicals, 14C-labeled Gd-DTPA and 55Fe-labeled red blood cells, will be used to validate MRI measurements by quantitative autoradiography and to establish plasma Gd-DTPA time-concentration curves. The hypothesis for Aim 2A is that HT occurs due to acute endothelial damage that causes BBB disruption. Contrast enhanced MRI of ischemic brain tissue using Gd-DTPA can demonstrate acute BBB injury, which precedes the development of HT, and provide quantitative estimates for BBB Gd-DTPA permeability surface product (PS product) and distribution space that may provide a useful risk index for HT. Aim 2B will be to investigate the effects of blood pressure, cerebral perfusion, cerebral blood flow (CBF) and infarct size on acute Gd-DTPA uptake and subsequent HT to test the hypothesis that the frequency and degree of Gd-DTPA uptake and subsequent HT will be affected by the perfusion status of the tissue and by larger, more severe ischemic infarcts. Aim 3 will be to examine whether the thrombolytic agent rt-PA increases the frequency and/or the severity of HT in the proposed rat MCAO model. The hypothesis for Aim 3 is that rt-PA will affect the severity of bleeding, and hence the size of the enhancing region and/or rate of Gd-DTPA uptake in acute phases of ischemia and reperfusion, but will not increase the frequency of HT in our rat MCAO model.