Blood‐mediated scavenging of cerebrospinal fluid glutamate

Abstract

The maintenance of brain extracellular glutamate (Glu) at levels below its excitotoxic threshold is performed by Glu transporters present on glia and neurons as well as on brain capillary endothelial cells which remove brain Glu into blood. The feasibility of accelerating the naturally occurring brainto-blood Glu efflux was studied using paradigms based on the fate of Glu present in the cerebrospinal fluid or infused into the brain ventricles and monitored before, during, and after decreasing blood Glu levels with pyruvate and oxaloacetate, the respective Glu co-substrates of the blood resident enzymes glutamate-pyruvate transaminase and glutamateoxaloacetate transaminase. Results from cerebroventricular perfusions with [ 3 H]Glu, intracerebroventricular injections of [ 3 H]Glu, and measurements of the basal CSF Glu levels point out to the same conclusion that the intravenous administration of pyruvate and oxaloacetate which decreases blood Glu levels accelerates the brain-to-blood Glu efflux. We conclude that the brain extracellular Glu levels can be controlled in part by the blood Glu levels. The results may provide not only a rational explanation for the inhibition of Glu release and neuroprotective effects of parentally administered pyruvate in hemorrhagic shock and forebrain ischemia but could also outline a potential strategy for the removal of excess Glu in various neurodegenerative disorders.

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

“…To exclude the possibility of a direct toxic effect of the OxAc treatment on glioma cells, a 3-(4,5-dimethyltiazol-2yl)-2,5-phenyl-2H-tetrazolium bromide (MTT) assay was performed on C6 cells exposed in-vitro to OxAc (3 μM–0.3 μM) for 24 h and no effect was found (data not shown). Considering our previous [4, 19–21] and current results using blood Glutamate scavenging in several animal models we suggest that the therapeutic effects of OxAc on glioma growth and invasiveness in vivo are due primarily to the scavenging effect of OxAc blood Glu. In the case of glioma, our results strengthen the concept that OxAc caused in increased efflux of peritumor Glu into the blood, slowing down the ability of the tumor to create the space for its expansion.…”

“…We have established [19] the feasibility of accelerating this naturally occurring brain to-blood Glu efflux by decreasing blood Glu levels with intravenous oxaloacetate (OxAc) or pyruvate, the respective Glu co-substrates of the blood resident enzymes glutamate–oxaloacetate transaminase (GOT) and glutamate–pyruvate transaminase (GPT). We later demonstrated that blood Glu scavenging provides highly significant brain neuroprotection since both OxAc and pyruvate improve the neurological status of rats submitted to close head injury [20–22].…”

“…This combination is required both for the administration of realistic concentrations of OxAc and for the fact that the basal GOT levels in blood are limiting [22]. In our previous studies, we intravenously injected rats with OxAc to reach a steady state concentration in blood [19]. However, one can maintain (as expected from the Michaelis-Menten equation) the same rate of blood Glu transamination by reducing significantly the concentration of the administered OxAc while increasing in parallel the GOT blood concentration.…”

High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke

“…According to this, the capacity of the enzyme glutamate oxaloacetate transaminase (GOT) to metabolize glutamate represents a strategy to decrease glutamate levels in blood (Gottlieb et al, 2003;Teichberg et al, 2009). In fact, we observed that oxaloacetate-mediated GOT activation in an animal model of ischemia induces a neuroprotective effect, thus showing this endogenous blood enzyme as a novel neuroprotective tool against ischemic stroke (Campos et al, 2011).…”

“…As ischemic stroke is associated with an excessive release of glutamate into the brain parenchyma (Castillo et al, 1996(Castillo et al, , 1997, a decrease in blood glutamate levels provides a mechanism to increase the gradient concentration and to remove this neurotransmitter from the brain at early times, with possible therapeutic implications after an ischemic insult (Gottlieb et al, 2003;Teichberg et al, 2009).…”