Pyruvate: Powerful Brain Protection after Cardiac Arrest

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DESCRIPTION (provided by applicant): The leading cause of death in the United States, cardiac arrest imposes profound ischemia on the brain and other internal organs. Even when cardiac rhythm is restored, most cardiac arrest victims eventually succumb to the devastating effects of irreversible brain damage, and many survivors suffer persistent, debilitating neurological impairment. Despite extensive preclinical and clinical research, a practical treatment to prevent brain damage in cardiac arrest victims remains elusive. Recently the hormone erythropoietin was shown to protect brain from ischemic injury by activating cytoprotective signaling cascades which suppress neuronal apoptosis and dampen destructive inflammation. However, because erythropoietin cannot readily traverse the blood-brain barrier, massive dosages are required to achieve significant neuroprotection, and outcomes of recent clinical trials of intravenous erythropoietin in cardiac arrest victims have been disappointing. Neurons and astrocytes can express and synthesize erythropoietin, and induction of erythropoietin expression within the brain could confer powerful neuroprotection while circumventing the blood brain barrier. Recently, we demonstrated that pyruvate, a natural intermediary metabolite and antioxidant, induced novel erythropoietin expression and signaling in arrested myocardium; importantly, these responses remained robust 4 hours after pyruvate had cleared. Moreover, intravenous pyruvate infusion during cardiopulmonary resuscitation (CPR) prevented subsequent neurological impairment and neuronal apoptosis 3 days after cardiac arrest. A high-affinity, high-capacity transport mechanism within the blood brain barrier efficiently delivers pyruvate to the brain parenchyma. This investigation will test the hypothesis that pyruvate prevents brain injury and preserves neurocognitive function after cardiac arrest by inducing erythropoietin expression and signaling within the brain. This hypothesis will be addressed in dogs subjected to ventricular fibrillation cardiac arrest, CPR, defibrillatory countershocks and recovery. Pyruvate or control NaCl will be infused intravenously during CPR and the first 55 min recovery, or in a delayed manner 120-180 min after restoration of cardiac rhythm and brain perfusion. Erythropoietin mRNA and protein content, signaling kinase activation, neutrophil infiltration, and activities of proapoptotic caspases, pro-inflammatory matrix metalloproteinases, and the cytoprotective enzyme endothelial nitric oxide synthase will be measured in vulnerable brain regions biopsied at 5 h, 2 d and 4 d after cardiac arrest-resuscitation. Crucial information on pyruvate's neuroprotective mechanisms and its ability to induce erythropoietin signaling within the brain will provide the essential foundation for eventual clinical exploitation of this cerebroprotective phenomenon. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because brain damage inflicted by cardiac arrest is a leading cause of death and permanent disability in the United States, yet there currently are no effective treatments to protect the brain from cardiac arrest. This investigation will test the idea that pyruvate prevents cardiac arrest-induced brain injury by activating production of erythropoietin within the brain. Thus, the proposed research is directly relevant to NINDS's mission to reduce the burden of neurological disease.