Blood Glutamate Scavenging: Insight into Neuroprotection

Abstract

Brain insults are characterized by a multitude of complex processes, of which glutamate release plays a major role. Deleterious excess of glutamate in the brain’s extracellular fluids stimulates glutamate receptors, which in turn lead to cell swelling, apoptosis, and neuronal death. These exacerbate neurological outcome. Approaches aimed at antagonizing the astrocytic and glial glutamate receptors have failed to demonstrate clinical benefit. Alternatively, eliminating excess glutamate from brain interstitial fluids by making use of the naturally occurring brain-to-blood glutamate efflux has been shown to be effective in various animal studies. This is facilitated by gradient driven transport across brain capillary endothelial glutamate transporters. Blood glutamate scavengers enhance this naturally occurring mechanism by reducing the blood glutamate concentration, thus increasing the rate at which excess glutamate is cleared. Blood glutamate scavenging is achieved by several mechanisms including: catalyzation of the enzymatic process involved in glutamate metabolism, redistribution of glutamate into tissue, and acute stress response. Regardless of the mechanism involved, decreased blood glutamate concentration is associated with improved neurological outcome. This review focuses on the physiological, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. We discuss the details of brain-to-blood glutamate efflux, auto-regulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. We then propose different applied methodologies to reduce blood and brain glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.

Microsomal Triglyceride Transfer Protein Inhibition Induces Endoplasmic Reticulum Stress and Increases Gene Transcription via Ire1α/cJun to Enhance Plasma ALT/AST

“…S3B), which can be taken up by RBCs through sodium-coupled transporters (37). Additionally, these reductions in plasma glutamate lower cerebrospinal fluid glutamate and therefore, provides protection against neurotoxicity (36). We did not evaluate these possibilities, but a few studies manipulating plasma glutamine, a precursor of glutamate, support this hypothesis.…”

“…Plasma glutamate is elevated in metabolic disorders such as NAFLD (34,35). However, excess glutamate is neurotoxic (36). Therefore, increases in plasma ALT/AST might reduce plasma glutamate by converting it to ␣-ketoglutarate (supplemental Fig.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Brain extracellular levels of glutamate are normally maintained in the micromolar range by EAATs but can rapidly increase 100-fold during microglial and macrophage release (Dantzer and Walker, 2014;Leibowitz et al, 2012). However, when glutamate concentrations become excessive through contributions from activated microglia and macrophages, the EAAT uptake mechanism may be insufficient to clear the entire glutamate load with further impairment of glutamate clearance (Gras et al, 2012;Takaki et al, 2012).…”

“…This in turn can be clinically accomplished by administering agents such as oxaloacetate and pyruvate that stimulate glutamatemetabolizing enzymes such as glutamate oxaloacetate and pyruvate transaminase (SGOT and SGPT) in the blood and lead to rapid depletion of blood glutamate. This strategy has met with some success in reducing glutamate-induced excitotoxicity following experimental induction of stroke (Leibowitz et al, 2012). More recently, this strategy of glutamate 'scavenging' has been proposed as a possible means to reduce excessive glutamate activity as a result of increased inflammation (Dantzer and Walker, 2014).…”

A novel mechanism of neuroprotection: Blood glutamate grabber

“…24 Alternatively, when extracellular concentrations become elevated, sodium-dependent transport located on the antiluminal surface of brain capillary endothelial cells is able to transfer glutamate from the extracellular space. 25 When glutamate accumulates in the endothelial cells to a concentration that exceeds plasma levels it is moved via facilitated diffusion through the luminal side into the blood stream ( Figure 1). In this regard, the endothelial regulation of CNS glutamate concentration can occur despite unfavorable concentration gradients from CNS to plasma.…”