Homeostasis of the Intraparenchymal-Blood Glutamate Concentration Gradient: Maintenance, Imbalance, and Regulation

Abstract

It is widely accepted that glutamate is the most important excitatory neurotransmitter in the central nervous system (CNS). However, there is also a large amount of glutamate in the blood. Generally, the concentration gradient of glutamate between intraparenchymal and blood environments is stable. However, this gradient is dramatically disrupted under a variety of pathological conditions, resulting in an amplifying cascade that causes a series of pathological reactions in the CNS and peripheral organs. This eventually seriously worsens a patient’s prognosis. These two “isolated” systems are rarely considered as a whole even though they mutually influence each other. In this review, we summarize what is currently known regarding the maintenance, imbalance and regulatory mechanisms that control the intraparenchymal-blood glutamate concentration gradient, discuss the interrelationships between these systems and further explore their significance in clinical practice.

Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

“…The Glu concentration in neuronal cytoplasm is ~5 mM, while astrocytic concentrations are lower (around 2–3 mM), however, Glu concentrations in cerebrospinal fluid or brain intercellular fluids range from 1 to 10 μM [65]. These concentrations are 5–50 fold lower than in the blood, giving rise to the intraparenchymal blood Glu concentration gradient, which depends on the ability of the blood brain barrier to prevent Glu entrance into the brain [66]. In the CNS, Glu is produced by neurons from transamination of α-ketoglutarate, originated in the tricarboxylic acid cycle, and from hydrolytic deamination of glutamine by phosphate-activated glutaminase [67].…”

“…Other approaches would include the discovery of modulators of the glycine site associated with NMDA receptors, of the reuptake systems, as well as of mGlu receptor allosteric modulators to provide fine tuning of the glutamatergic neurotransmission [9,41,110]. Another fundamental issue, in view of the stringent relationship existing between the effects of Glu and the maintenance of the steep extracellular/intracellular concentration gradient, consists in evaluating whether conditions leading to the disruption of the blood brain barrier or the gut blood barrier, such as those induced by dysbiosis or stress, may induce excessive increase of extracellular Glu levels, sustaining development of either CNS and/or ENS disorders, as observed after brain and gut injury [66,99].…”

d-glutamate and Gut Microbiota in Alzheimer’s Disease

“…Brain capillary endothelial cells can mediate brain-to-blood glutamate efflux [55,56]. Glutamate concentrations are 5-50-fold lower in the blood, and this concentration gradient prevents glutamate entry to the brain [57]. The two membranes of the BBB include luminal (blood facing) and abluminal (brain facing) membranes which work in a complementary fashion.…”

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

“…In astrocytes, through glutamate dehydrogenase, glutamate contributes to the tricarboxylic cycle intermediate α-ketoglutarate and ATP production after brain ischemia [73]. Extracellular presence of glutamate is excitotoxic since it provokes the activation of glutamate receptors in the post-synaptic membrane, leading to the destruction of the calcium buffer system, mitochondria damage, and inhibition of phosphatidylcholine-specific phospholipase C [74]. High levels of glutamate in the interstitial fluid can be a consequence of neural or glial destruction [74].…”

“…Extracellular presence of glutamate is excitotoxic since it provokes the activation of glutamate receptors in the post-synaptic membrane, leading to the destruction of the calcium buffer system, mitochondria damage, and inhibition of phosphatidylcholine-specific phospholipase C [74]. High levels of glutamate in the interstitial fluid can be a consequence of neural or glial destruction [74]. In hydrocephalic hyh mice treated with BM-MSC, glycine, phosphatidylethanolamine, taurine, and threonine, which are considered osmoregulatory metabolites [75,76], were found following the same trends as glutamine and glutamate.…”