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.
Highlights
Glutamate, a known excitatory neurotransmitter in the central nervous system (CNS), is a non-essential amino acid, and is the most abundant free amino acid in the CNS, accounting for approximately 60 percent of total neurotransmitter activity in the brain
Animal models and human clinical studies reveal the association of pathologically elevated extracellular fluid (ECF) glutamate levels and several acute and chronic neurodegenerative disorders, including stroke [12], traumatic brain injury (TBI) [13], intracerebral hemorrhage [14], meningitis, brain hypoxia [15], amyotrophic lateral sclerosis (ALS) [16], glaucoma [17], HIV
Considering that the placenta has a well-developed system of transporters for glutamate elimination, it seems plausible that one may create a favorable chain of glutamate concentration gradients that would lead to the elimination of excess glutamate from the fetal brain
Summary
A known excitatory neurotransmitter in the central nervous system (CNS), is a non-essential amino acid, and is the most abundant free amino acid in the CNS, accounting for approximately 60 percent of total neurotransmitter activity in the brain. Removal of glutamate from brain ECF into blood is attributed to the existence of the abluminal glutamate transporters, and the highly vascularized nature of the brain, which is comprised of an extensive network of capillary blood vessels, with an average capillary-to-capillary distance of 19 ± 4 μm, a total capillary surface of 12 m2, and an average capillary distance of 8–20 μm This vascular network accounts for the proportionally high cerebral blood (reaching 20% of total cardiac output), which allows this mechanism to be effective [33,34,35]. Recent research applies different strategies for minimizing the toxic effects of glutamate in the context of ischemic stroke and traumatic brain injury (TBI) This provides neuroprotection, including: inhibiting glutamate synthesis, blocking its release from presynaptic terminals, antagonizing its actions on postsynaptic receptors, and accelerating its reuptake from the synaptic cleft. Blood glutamate scavengers should preserve the physiological effects of glutamate in regulating the metabolic and electrolyte balance, maintaining neuronal function
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