Abstract 508: Pyruvate Induction of Glyoxalase 1 in Porcine Brain Post-cardiac Arrest: Enhanced Methylglyoxal and Glutamate Detoxification

Abstract

Background: After cardiac arrest (CA) and cardio-cerebral resuscitation (CCR), enhanced glycolysis elevates toxic methylglyoxal (MG) that contributes to carbonyl-exacerbated oxidative stress, enzyme inactivation and death of neurons and astroglia. Post cardiac arrest cognitive deficits may be prevented by pyruvate infusions that boost glyoxalase 1 (GLO1) detoxification of MG and brain glutamate efflux via Nrf2-regulated Phase II gene expression.

Purpose: To define pyruvate-induced cytoprotective mechanisms that curtail brain injury and cognitive deficit after cardiac arrest and resuscitation in pigs.

Methods: Pigs were subjected to CA/CCR, infused with 4 mM pyruvate or NaCl control, then carotid artery and frontal cortical lysates were assayed for Nrf2/ARE binding activity and GLO1 activity, while plasma glutamate concentrations were measured.

Results: Compared with saline controls, pyruvate infused pigs demonstrated increased Nrf2/ARE binding activity and 3-fold higher GLO1 activity supporting MG detoxification. Plasma glutamate concentrations were substantially reduced by pyruvate, which would support greater brain efflux of excitotoxic glutamate.

Conclusions: Intravenous pyruvate induces Nrf2-regulated gene activation for augmented GLO1 biological activity via mechanisms that may lower glutamate-inflicted excitotoxicity and the heretofore untreatable cognitive deficits.