Pyruvate induction of Nrf2/ARE-regulated Glyoxalase1 and Glutathione Reductase in porcine brain post-cardiac arrest: enhanced methylglyoxal detoxification

Abstract Pyruvate induction of Nrf2/ARE-regulated Glyoxalase1 and Glutathione Reductase in porcine brain post-cardiac arrest:enhanced methylglyoxal detoxification.Background:After cardiac arrest (CA) and cardio-cerebral resuscitation (CCR), enhanced glycolysis elevates toxic carbonyl methylglyoxal (MG) that contributes to reactive oxidative/nitrosative stress (RONS), 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 glutathione (GSH) synthesis by glutathione reductase (GR) via Nrf2/ARE (antioxidant response element)-regulated Phase II gene expression.Hypothesis:Pyruvate-induced cytoprotective mechanisms can curtail brain injury and cognitive deficit after cardiac arrest and resuscitation in pigs.Methods:Compared to sham non-arrest animals, pigs were subjected to CA/CCR, infused with either 4 mM pyruvate or NaCl for one hour, recovered 4 hours prior to sacrifice. Post-mortem frontal cortical lysates were assayed for Nrf2/ARE binding activity, GLO1, GR, and GAPDH (rate-limiting for MG production) activity, while plasma glutamate concentrations were measured.Results:Compared with saline controls, pyruvate infused pigs demonstrated increased Nrf2/ARE binding activity (Fig 1) and 3-fold higher GLO1 activity (Fig 2) supporting MG detoxification, while GR (Fig 3) and GAPDH (Fig 4) were similarly stimulated. Plasma glutamate concentrations were reduced by pyruvate (Fig 5), which would support greater brain clearance of excitotoxic glutamate, according to the brain-to-blood glutamate efflux hypothesis.Conclusions:Intravenous pyruvate induces Nrf2-regulated gene activation for augmented GR, and GLO1 biological activity via mechanisms that may lower glutamate-inflicted excitotoxicity and heretofore untreatable cognitive deficits of post-CA/CCR brain injury.Thus pyruvate infusion may also provide therapeutic benefit for several neurodegenerative disorders of similar etiology.