The primary objective of this research is to asses the efficacy and mechanism of action of clinically relevant neuronal protective pharmacotherapies aimed at preventing disturbances in calcium activated enzyme systems after reversible cerebral ischemia. Despite promising results in animal stroke models, there is still no clinically proven effective therapy for acute stroke, the third most common cause of death in the U.S. This dilemma may be explained in part by a poor correlation between the design of preclinical and clinical efficacy studies In this research, we hope to reconcile some of these differences by trying as much as possible to model important components of clinical stroke, in particular reperfusion, its occurrence, timing, and consequences. In order to carry out this work, we have determined the temporal thresholds before which neuronal protective therapies must be started to be effective. We will be establishing a duration of ischemia vs. severity of damage """"""""dose-response"""""""" curve to see if it can be shifted favorably by therapy. Both histological and functional outcomes will be measured. We will also be producing severe and predictable amounts of edema during reperfusion to see if it too can be limited by therapy. The therapies we are evaluating are based on preliminary data indicating efficacy at doses tolerated in man, and a mechanism of action though to ameliorate disturbances in calcium metabolism by impacted specific steps in the cascade of post-ischemic glutamate excitotoxicity. This work should help to identify pharmacotherapies and therapeutic strategies most likely to lead to success in clinical trials for hyperacute stroke. The second major aim of this work is to explore the relationship of Cam-K-II to ischemic injury. Cam-K-II is the most abundant protein kinase in the brain and is activated by increases in intracellular calcium caused, in part, by increased extracellular glutamate and activation of the NMDA receptor. We have shown that persistent downregulation of Cam-K-II activity due to enzyme translocation is associated with irreversible neuronal damage. We will study the nature and reversibility of this translocation which may lead to new strategies for neuronal protective intervention.
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