Abstract Title

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

Presenter Name

Anh Q Nguyen

RAD Assignment Number

319

Abstract

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 < 0.05) during CA + CPR with NaCl and Na-pyruvate treatment, while no appreciable difference was detected in the cerebellum. There were no statistically significant differences in HIF-1α or EPO contents in the hippocampus among the sham and CA groups. Similar trends were observed in the cerebellum except for EPO content, which fell by 40% (PConclusion: Cardiac arrest inactivates aconitase and depletes cytoprotective EPO in ischemia-sensitive brain regions. Although pyruvate intervention during CPR and the initial 60 min recovery did not produce sustained protection or upregulation of aconitase or EPO, it produced robust augmentation of glyoxalase-1, thereby bolstering the brain’s defenses against the glycating metabolite methylglyoxal.

Presentation Type

Poster

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

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 < 0.05) during CA + CPR with NaCl and Na-pyruvate treatment, while no appreciable difference was detected in the cerebellum. There were no statistically significant differences in HIF-1α or EPO contents in the hippocampus among the sham and CA groups. Similar trends were observed in the cerebellum except for EPO content, which fell by 40% (PConclusion: Cardiac arrest inactivates aconitase and depletes cytoprotective EPO in ischemia-sensitive brain regions. Although pyruvate intervention during CPR and the initial 60 min recovery did not produce sustained protection or upregulation of aconitase or EPO, it produced robust augmentation of glyoxalase-1, thereby bolstering the brain’s defenses against the glycating metabolite methylglyoxal.