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

Abstract

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. AbstractCardiac 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.

Pyruvate and lactate as local prognostic biomarkers of patient outcome after achilles tendon rupture

“…The relationship between increased pyruvate‐r and less tiredness, reduced stiffness and less limitations in strength in the injured limb suggests that pyruvate is involved in healing pathways leading to improved mechanical properties, for example, by conversion of collagen type III (scar tissue) into collagen type I (mature tissue). Pyruvate is known among other things to promote wound healing by augmenting the antioxidant response of the tissue and acting antifibrotically, which minimizes the fibrotic collagen type III . The finding of less experience of pain related to higher pyruvate‐r may reflect the fact that pyruvate reduces fibrosis and inflammation.…”

“…Interestingly, addition of pyruvate after injury has recently been demonstrated to exhibit strong anti‐inflammatory and anti‐oxidative effects in tissue repair. Thus, brain function after post‐ischemic myocardial arrest in pigs was improved by the use of pyruvate infusion, which lowered the oxidative stress . Oxidative stress has clearly been shown to impair the mechanical behavior of tendon collagen fibrils, which suggests that pyruvate may counteract the oxidative stress also to improve the mechanical properties in tendon healing …”

“…Pyruvate is known among other things to promote wound healing by augmenting the antioxidant response of the tissue and acting antifibrotically, which minimizes the fibrotic collagen type III. 9,21,22 The finding of less experience of pain related to higher pyruvate-r may reflect the fact that pyruvate reduces fibrosis and inflammation. Interestingly, addition of pyruvate after injury has recently been demonstrated to exhibit strong anti-inflammatory and anti-oxidative effects in tissue repair.…”

“…Thus, brain function after post-ischemic myocardial arrest in pigs was improved by the use of pyruvate infusion, which lowered the oxidative stress. 9 Oxidative stress has clearly been shown to impair the mechanical behavior of tendon collagen fibrils, which suggests that pyruvate may counteract the oxidative stress also to improve the mechanical properties in tendon healing. 23 Pyruvate-r was found related not only to the patient-reported outcome measures, but additionally to the functional outcome of the patients, which further supports the importance of pyruvate in the tendon healing process.…”

“…8 Pyruvate is an essential metabolite in the cell energy metabolism known to promote wound healing by reducing fibrosis and enhancing the expression of antioxidant enzymes. 9 Pyruvate is intimately related to lactate, which is upregulated under anaerobic conditions when pyruvate is reduced to lactate by lactate dehydrogenase. 10 Lactate is better known as a hypoxic marker, but has been also shown to enhance tendon healing by improving collagen synthesis.…”