MRI is a sensitive and clinically relevant method for monitoring ischemic brain injury in vivo. However, the correlation between MRI parameters and the underlying pathophysiology remain unclear. Our overall goal is to define acute excitotoxic events in ischemia and reperfusion, correlate these events to chronic outcomes measured with MRI, and examine how these correlations chance in response to neuroprotective therapy. To achieve this, we propose the following studies. These studies will be useful in understanding how MRI outcomes correlate with underlying neurochemical alterations in experimental stroke. 1. Definition of Acute Excitotoxic Events. The excitotoxic theory postulates that glutamate elevations during ischemia lead to neuronal death. However, post-ischemic neurotransmitter chances also may be important. Glutamate levels are rapidly normalized upon recirculation, but damage continues to evolve and treatment with glutamate antagonists continue to be effective post-ischemia. Furthermore, the excitotoxic theory does not fully address the pan-necrosis and infarction that occurs in stroke. It is possible that perturbations in glial function contribute to the development of infarction. Our pilot data suggest that large secondary elevations in glutamate occur during reperfusion. We hypothesize that primary glutamate elevations are due to ischemic depolarization whereas secondary elevations are due to failure of glial reuptake function. We will test this hypothesis using a rabbit model of focal ischemia. Acute transmitter dynamics will be measured with in vivo microdialysis. In order to distinguish between neuronal and glial mechanisms of glutamate release, we will use w-conotoxins and threohydroxyaspartate to block neuronal release and glial reuptake, respectively. 2. Use of MRI to Predict Histological Outcome. Our pilot data shows that, by combining multiple MRI techniques, we may be able to monitor the evolution of damage from initial edema into complete infarction. In order to quantitatively map the temporal profile of injury, we will use a rat focal ischemia model and compare quantitative MRI with histologic outcomes of neuronal (H+E), glial (anti-GFAP) and BBB (anti-serum protein) damage, focussing on the evolution from intermediate (day 3) to chronic (day 7) stage after ischemia. 3. Effects of Neuroprotective Therapy on Acute Excitotoxic Events and Chronic MRI Outcomes. Based on our pilot data. We propose that both primary and secondary glutamate elevations contribute to infarction after transient focal ischemia. Therefore, both primary and secondary events must be antagonized for maximal neuroprotection. We will test this hypothesis by comparing acute excitotoxic changes to chronic outcomes with and without therapy. A rat focal ischemia model will be used. Acute chances will be measured with microdialysis and intermediate-to-chronic outcomes will be monitored with MRI. We will test the effects of glutamate antagonists (MK801 and NBQX) and inhibitors of lactic acidosis (dichloroacetate).
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