title: Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest.
abstract: Cardiac arrest (CA) and cardiocerebral resuscitation (CCR)-induced ischemia-reperfusion imposes oxidative and carbonyl stress that injures the brain. The ischemic shift to anaerobic glycolysis, combined with oxyradical inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), provokes excessive formation of the powerful glycating agent, methylglyoxal. The glyoxalase (GLO) system, comprising the enzymes glyoxalase 1 (GLO1) and GLO2, utilizes reduced glutathione (GSH) supplied by glutathione reductase (GR) to detoxify methylglyoxal resulting in reduced protein glycation. Pyruvate, a natural antioxidant that augments GSH redox status, could sustain the GLO system in the face of ischemia-reperfusion. This study assessed the impact of CA-CCR on the cerebral GLO system and pyruvate's ability to preserve this neuroprotective system following CA. Domestic swine were subjected to 10 min CA, 4 min closed-chest CCR, defibrillation and 4 h recovery, or to a non-CA sham protocol. Sodium pyruvate or NaCl control was infused (0.1 mmol/kg/min, intravenous) throughout CCR and the first 60 min recovery. Protein glycation, GLO1 content, and activities of GLO1, GR, and GAPDH were analyzed in frontal cortex biopsied at 4 h recovery. CA-CCR produced marked protein glycation which was attenuated by pyruvate treatment. GLO1, GR, and GAPDH activities fell by 86, 55, and 30%, respectively, after CA-CCR with NaCl infusion. Pyruvate prevented inactivation of all three enzymes. CA-CCR sharply lowered GLO1 monomer content with commensurate formation of higher molecular weight immunoreactivity; pyruvate preserved GLO1 monomers. Thus, ischemia-reperfusion imposed by CA-CCR disabled the brain's antiglycation defenses. Pyruvate preserved these enzyme systems that protect the brain from glycation stress. Impact statement Recent studies have demonstrated a pivotal role of protein glycation in brain injury. Methylglyoxal, a by-product of glycolysis and a powerful glycating agent in brain, is detoxified by the glutathione-catalyzed glyoxalase (GLO) system, but the impact of cardiac arrest (CA) and cardiocerebral resuscitation (CCR) on the brain's antiglycation defenses is unknown. This study in a swine model of CA and CCR demonstrated for the first time that the intense cerebral ischemia-reperfusion imposed by CA-resuscitation disabled glyoxalase-1 and glutathione reductase (GR), the source of glutathione for methylglyoxal detoxification. Moreover, intravenous administration of pyruvate, a redox-active intermediary metabolite and antioxidant in brain, prevented inactivation of glyoxalase-1 and GR and blunted protein glycation in cerebral cortex. These findings in a large mammal are first evidence of GLO inactivation and the resultant cerebral protein glycation after CA-resuscitation, and identify novel actions of pyruvate to minimize protein glycation in postischemic brain.
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Scott
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Nguyen
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Cherry
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Hollrah
authors.affiliation: 2 Department of Biological Sciences, St. Mary's University, San Antonio, TX 78228, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Salinas
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Williams
authors.affiliation: 3 Department of Medical Laboratory Sciences, Tarleton State University, Fort Worth, TX 76107, USA.
authors.forename: Myoung-Gwi
authors.initials: MG
authors.lastname: Ryou
authors.affiliation: 1 Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Mallet
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005980:Glutathione Reductase / Q000032:analysis; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000032:analysis; D006031:Glycosylation; D006323:Heart Arrest / Q000628:therapy*; D007791:Lactoylglutathione Lyase / Q000032:analysis; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress; D011765:Pyruvaldehyde / Q000633:toxicity*; D019289:Pyruvic Acid / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000517:prevention & control*; D012151:Resuscitation / Q000009:adverse effects*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D011765:Pyruvaldehyde; D019289:Pyruvic Acid; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D005980:Glutathione Reductase; D007791:Lactoylglutathione Lyase
keywords: Glutathione; glycation; glyoxalase-1; methylglyoxal; nuclear factor erythroid 2-related factor 2; swine