Ischemic Postconditioning Protection of Hippocampal CA1 Neurons

Transient global cerebral ischemia (GCI) during cardiac arrest affects 300,000 Americans each year, and in many cases, results in delayed death of hippocampal CA1 neurons and severe cognitive deficits. Current therapies are ineffective and only offer a short therapeutic window. Studies are therefore needed that would help elucidate potential new ways to save neurons following GCI and significantly extend the therapeutic window. Intriguingly, recent work in animal models has shown that ischemic postconditioning (Post C) up to 2 days following GCI can save up to 70-90% of neurons in the hippocampal CA1 region. This exciting observation has led to hope that further studies on the mechanisms underlying Post C neuroprotection following GCI could potentially lead to new therapies in humans, which would allow rescue of hippocampal CA1 neurons in the human brain following cardiac arrest with a dramatically extended therapeutic window. The overall goal of the current proposal is to elucidate how Post C protects the brain following GCI. Our overall hypothesis is that Post C neuroprotection is mediated by an NADPH oxidase-mediated burst of superoxide anions, which leads to activation of the nuclear factor E2-related factor 2 (Nrf2), with subsequent enhanced expression of Nrf2-dependent detoxifying/antioxidant genes, which prevents delayed neuronal cell death. Our preliminary data leads us to further hypothesize that NR2A-containing NMDA receptors mediate the Post C-induced NADPH oxidase activation and neuroprotection. Specific Aim 1. To determine the role of NADPH oxidase and superoxide in Post C-induced neuroprotection. Specific Aim 2. To establish the role and therapeutic efficacy of targeting the NMDA 2A receptor signaling pathway for Post C neuroprotection. Specific Aim 3. To determine whether the critical downstream effector mechanism for Post C neuroprotection involves activation of the Nrf2 antioxidant defense system, and explore the therapeutic potential of targeting this pathway. (AHA Program: Grant-in-Aid)