Cardiac arrest (CA) occurs in approximately 600,000 people each year in the United States alone and is a major cause of mortality and morbidity1. Cardiac arrest results in global cerebral ischemia and hypoxic-ischemic injury, and the consequent neuronal damage results in long-term cognitive impairments. The memory disorders commonly observed following CA are readily explained by the selective vulnerability of CA1 pyramidal cells of the hippocampus. However, recent imaging studies in humans indicate that hippocampal injury per se may not correlate with memory dysfunction9, implicating altered physiology following ischemia. Indeed, our recent study indicates that surviving neurons in the hippocampus exhibit physiological changes that likely contribute to cognitive deficits10. This is significant because several interventional clinical trials aimed at reducing neuronal injury have failed to improve outcome following ischemic insults, making it clear that alternative approaches are needed to improve functional recovery. An optimal therapeutic intervention would have the capacity to reduce neuronal injury, maintain functional neuronal networks, and even recover function if administered in the subacute to late chronic phase. Our preliminary data indicate that inhibition of the ion channel TRPM2 fits these criteria. We show that inhibition of TRPM2 during the acute phase (30 min) after cardiac arrest provides neuroprotection and delayed inhibition (6-7 days) reverses CA-induced impairment of neuronal function and plasticity. Memory deficits and hippocampal dysfunction are well accepted sequelae of global cerebral ischemia. Evidence of hippocampal dysfunction following ischemia is provided using electrophysiological recordings of the remaining synaptic network. Synaptic plasticity, in the form of strengthening following physiological stimuli (long-term potentiation; LTP) is a well-established cellular model of learnin and memory. Our recent studies and preliminary studies indicate that CA/CPR causes prolonged impairment (at least 30 days) of hippocampal LTP10 that is prevented by inhibition of TRPM2 channels during the acute phase (30 min) after CA/CPR. Most surprisingly, inhibition of TRPM2 one week after CA/CPR results in reversal of deficits in LTP and enhance memory function. TRPM2 channels have recently been observed to contribute to synaptic inhibition via activation of glycogen synthase kinase 3? (GSK3?); therefore we hypothesize that prolonged activation of TRPM2 channels within hippocampal synapses activates GSK3?, thereby inhibiting the induction of LTP and thus new memories. Our new preliminary data indicates that inhibition of TRPM2 has the potential reduce cognitive impairments and potentially provide a new restorative therapy. The current proposal is aimed at determining the mechanism underlying the regulation of TRPM2 channels during the subacute and chronic phase following ischemia and most-importantly the mechanism of TRPM2-mediated inhibition of synaptic plasticity. We hypothesize that 1) ischemia causes sustained activation of TRPM2 channels, 2) inhibiting synaptic plasticity and 3) that delayed administration of TRPM2 inhibitors will reverse deficits in synaptic plasticity and recover memory function following cardiac arrest.
Cardiac arrest and consequent cerebral ischemia is one of the leading causes of death and disability in the United States. Unfortunately, there are currently no drugs available to improve outcome and quality of life following severe heart attack. The proposed studies will demonstrate for the first time that sustained activation of synaptic TRPM2 channels contributes to ischemia-induced neuronal dysfunction and suggest a novel interventional strategy to improve outcome following cardiac arrest.
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