Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest

Gary F. Scott, Anh Q. Nguyen, Brandon H. Cherry, Roger A. Hollrah, Isabella Salinas, Arthur G. Williams, Myoung Gwi Ryou, Robert T. Mallet

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)1095-1103
Number of pages9
JournalExperimental Biology and Medicine
Volume242
Issue number10
DOIs
StatePublished - 2017

Keywords

  • Glutathione
  • glycation
  • glyoxalase-1
  • methylglyoxal
  • nuclear factor erythroid 2-related factor 2
  • swine

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    Scott, G. F., Nguyen, A. Q., Cherry, B. H., Hollrah, R. A., Salinas, I., Williams, A. G., Ryou, M. G., & Mallet, R. T. (2017). Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest. Experimental Biology and Medicine, 242(10), 1095-1103. https://doi.org/10.1177/1535370217703353