Pyruvate’s blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke

Abstract

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.

Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment

“…We suggest that a possible neuroprotective mechanism of pyruvate could be explained by blood Glu scavenging activity, which causes the elimination of excessive Glu from the brain. Intravenous pyruvate has been shown to activate the blood plasma resident enzyme Glu-pyruvate transaminase, to cause a decrease of blood and brain Glu levels (though not as effectively as OxAc) and to display neuroprotective properties in animal models of traumatic brain injury [30,36] and permanent ischemia [37]. …”

The Link between Early Biomarker Analysis and the Neurological Outcome in Stroke Patients

“…GPT metabolizes glutamate in the peripheral blood, possibly reducing the risk of excitotoxicity [21,33]. In rats, GPT was proven to exert neuroprotective effects due to breakdown of glutamate in the peripheral blood [34,35]. D-dimer was the only biomarker significant in the group of the haemostatic biomarkers.…”

A novel mechanism of neuroprotection: Blood glutamate grabber

“…50 Similarly, in experimental studies, OxAc presented stronger protective effects than pyruvate. 57,58 Hemodialysis and peritoneal dialysis Another interesting and potentially useful method for reducing blood glutamate concentrations is the use of dialysis to filter the blood and remove excess glutamate. Compared with healthy controls, patients with endstage renal failure on hemodialysis had higher concentrations of blood glutamate.…”