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CaMKII and Ischemia

Glutamate toxicity is considered the early initiator of ischemic neuronal damage, being the spark that results in the stimulation of various injury mechanisms. Indeed, glutamate receptor inhibitors provide robust neuroprotection in animal models of cerebral ischemia, but have failed to translate in clinical stroke trials, due to unwanted side effects of blocking glutamatergic neurotransmission and narrow therapeutic window of opportunity. We propose an alternative approach to neuroprotection by targeting a modulator of glutamate neurotransmission (CaMKII) that will dampen excessive glutamate signaling, but not abolish physiological signaling, thus minimizing adverse side effects. Further, the use of inhibitors of excitotoxicity in the context of cardiac arrest-induced cerebral ischemia is a significant improvement as the timing to treatment is significantly shorter than in the setting of stroke, allowing early interventions to be clinically relevant. In collaboration with the laboratory of Dr. Ulli Bayer, we have begun investigating the neuroprotective potential of novel CaMKII inhibitors following cardiac arrest. Furthermore, these studies will lead to deeper insights into the effects of global ischemia on synaptic function and the cellular and molecular levels.