Cytoprotective and Anti-Glycation Defenses in Porcine Brain after Cardiac Arrest and Cardiocerebral Resuscitation

Ryou, Myoung-Gwi
Nguyen, Anh
Hollrah, Roger
Williams, Jr., Arthur
Scott, Gary
Olivencia-Yurvati, Albert
Mallet, Robert T.
Nguyen, Anh
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Cardiac arrest (CA) is often lethal, and survivors often face sequelae that greatly impact quality of life due to brain injury inflicted by ischemia-reperfusion. Effective cardiocerebral resuscitation (CCR) is essential for survival and recovery from CA. The complexity of the injury cascades ignited by CA and the presence of the blood-brain barrier challenge the development of pharmacological interventions to protect the brain. Our goal is to identify a blood-brain barrier-permeable intervention that mitigates CA-induced brain damage and, thus, fosters neurological recovery. Pyruvate, a cellular metabolite, energy substrate and antioxidant, has been found to be neuroprotective in a rat stroke model via induction of the cytoprotective cytokine erythropoietin (EPO). Hypothesis: Pyruvate treatment during CCR and post resuscitation decreases brain injury by upregulating cellular defense mechanisms including hypoxia inducible factor-1α (HIF-1α), EPO, the product of HIF-1 α’s gene program, and glyoxalase-1, the principal component of the brain’s defenses against the powerful glycating agent and glycolytic byproduct, methylglyoxal. Methods: Yorkshire swine (25-35 kg, both genders) were subjected to sham protocol (n = 6) or pacing-induced CA (n = 12). CCR was administered by precordial chest compressions (100/min) at 10-14 min CA, and transthoracic countershocks were applied to restore sinus rhythm. NaCl (n = 6) or Na-pyruvate (n = 6) was infused iv (0.1 mmol/kg/min) during CCR and the first 60 min recovery. At 4 h recovery, brain was cross-perfused with 0.9% NaCl, and then brain biopsies were freeze-clamped for biochemical analysis or fixed in 10% formalin for immunohistochemistry. Results: In hippocampus, activity of the oxyradical-sensitive TCA cycle enzyme aconitase fell by 50% (P

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