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 2 A 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 2 B 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.
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