Glutamate Abstracts 1

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Resveratrol prevents ammonia toxicity in astroglial cells.
            (Bobermin et al., 2012)  Download
Ammonia is implicated as a neurotoxin in brain metabolic disorders associated with hyperammonemia. Acute ammonia toxicity can be mediated by an excitotoxic mechanism, oxidative stress and nitric oxide (NO) production. Astrocytes interact with neurons, providing metabolic support and protecting against oxidative stress and excitotoxicity. Astrocytes also convert excess ammonia and glutamate into glutamine via glutamine synthetase (GS). Resveratrol, a polyphenol found in grapes and red wines, exhibits antioxidant and anti-inflammatory properties and modulates glial functions, such as glutamate metabolism. We investigated the effect of resveratrol on the production of reactive oxygen species (ROS), GS activity, S100B secretion, TNF-α, IL-1β and IL-6 levels in astroglial cells exposed to ammonia. Ammonia induced oxidative stress, decreased GS activity and increased cytokines release, probably by a mechanism dependent on protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways. Resveratrol prevented ammonia toxicity by modulating oxidative stress, glial and inflammatory responses. The ERK and nuclear factor-κB (NF-κB) are involved in the protective effect of resveratrol on cytokines proinflammatory release. In contrast, other antioxidants (e.g., ascorbic acid and trolox) were not effective against hyperammonemia. Thus, resveratrol could be used to protect against ammonia-induced neurotoxicity.

Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.
            (Boyko et al., 2011)  Download
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.

Brain to blood glutamate scavenging as a novel therapeutic modality: a review.
            (Boyko et al., 2014)  Download
It is well known that abnormally elevated glutamate levels in the brain are associated with secondary brain injury following acute and chronic brain insults. As such, a tight regulation of brain glutamate concentrations is of utmost importance in preventing the neurodegenerative effects of excess glutamate. There has been much effort in recent years to better understand the mechanisms by which glutamate is reduced in the brain to non-toxic concentrations, and in how to safely accelerate these mechanisms. Blood glutamate scavengers such as oxaloacetate, pyruvate, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase have been shown to reduce blood glutamate concentrations, thereby increasing the driving force of the brain to blood glutamate efflux and subsequently reducing brain glutamate levels. In the past decade, blood glutamate scavengers have gained increasing international interest, and its uses have been applied to a wide range of experimental contexts in animal models of traumatic brain injury, ischemic stroke, subarachnoid hemorrhage, epilepsy, migraine, and malignant gliomas. Although glutamate scavengers have not yet been used in humans, there is increasing evidence that their use may provide effective and exciting new therapeutic modalities. Here, we review the laboratory evidence for the use of blood glutamate scavengers. Other experimental neuroprotective treatments thought to scavenge blood glutamate, including estrogen and progesterone, beta-adrenergic activation, hypothermia, insulin and glucagon, and hemodialysis and peritoneal dialysis are also discussed. The evidence reviewed here will hopefully pave the way for future clinical trials.


 

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
            (Bravo et al., 2011)  Download
There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

Metabolic fate and function of dietary glutamate in the gut.
            (Burrin and Stoll, 2009)  Download
Glutamate is a main constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabolized in first pass by the intestine. Glutamate also is an important precursor for bioactive molecules, including glutathione, and functions as a key neurotransmitter. The dominant role of glutamate as an oxidative fuel may have therapeutic potential for improving function of the infant gut, which exhibits a high rate of epithelial cell turnover. Our recent studies in infant pigs show that when glutamate is fed at higher (4-fold) than normal dietary quantities, most glutamate molecules are either oxidized or metabolized by the mucosa into other nonessential amino acids. Glutamate is not considered to be a dietary essential, but recent studies suggest that the level of glutamate in the diet can affect the oxidation of some essential amino acids, namely leucine. Given that substantial oxidation of leucine occurs in the gut, ongoing studies are investigating whether dietary glutamate affects the oxidation of leucine in the intestinal epithelial cells. Our studies also suggest that at high dietary intakes, free glutamate may be absorbed by the stomach as well as the small intestine, thus implicating the gastric mucosa in the metabolism of dietary glutamate. Glutamate is a key excitatory amino acid, and metabolism and neural sensing of dietary glutamate in the developing gastric mucosa, which is poorly developed in premature infants, may play a functional role in gastric emptying. These and other recent reports raise the question as to the metabolic role of glutamate in gastric function. The physiologic significance of glutamate as an oxidative fuel and its potential role in gastric function during infancy are discussed.

L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity.
            (Felipo et al., 1994b)  Download
We have shown that acute ammonia toxicity is mediated by activation of the NMDA type of glutamate receptors. Although it is well known that L-carnitine prevents acute ammonia toxicity, the underlying molecular mechanism is not clear. We suspected that L-carnitine would prevent ammonia toxicity by preventing the toxic effects of glutamate. We have tested this hypothesis using primary cultures of neurons. L-carnitine prevented glutamate neurotoxicity in a dose-dependent manner similar to that required to prevent ammonia toxicity in animals. It is also shown that L-carnitine increases selectively the affinity of glutamate for the quisqualate type of glutamate receptors, while the affinity for the kainate and NMDA receptors is slightly decreased. L-carnitine prevents the increase in cytoplasmic Ca2+ induced by addition of glutamate. The Ca2+ levels rose 4.8-fold following addition of 1 mM glutamate, however, when the neurons were incubated previously with 5 mM L-carnitine, the Ca2+ levels increased only by 50%. Also, AP-3, an antagonist of the metabotropic receptor prevents the protective effect of L-carnitine against glutamate neurotoxicity. We suggest, therefore, that the protective effect of L-carnitine against glutamate toxicity is due to the increased affinity of glutamate for the metabotropic receptor. This mechanism could also explain the protection by L-carnitine against acute ammonia toxicity.

Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine.
            (Felipo et al., 1994a)  Download
In summary, we propose that acute ammonia intoxication leads to increased extracellular concentration of glutamate in brain and results in activation of the NMDA receptor. Activation of this receptor mediates ATP depletion and ammonia toxicity since blocking the NMDA receptor with MK-801 prevents both phenomena. Ammonia-induced metabolic alterations (in glycogen, glucose, pyruvate, lactate, glutamine, glutamate, etc) are not prevented by MK-801 and, therefore, it seems that they do not play a direct role in ammonia-induced ATP depletion nor in the molecular mechanism of acute ammonia toxicity. The above results suggest that ammonia-induced ATP depletion is due to activation of Na+/K(+)-ATPase, which, in turn, is a consequence of decreased phosphorylation by protein kinase C. This can be due to decreased activity of PKC or to increased activity of a protein phosphatase. We also show that L-carnitine prevents glutamate toxicity in primary neuronal cultures. The results shown indicate that carnitine increases the affinity of glutamate for the quisqualate type (including metabotropic) of glutamate receptors. Also, blocking the metabotropic receptor with AP-3 prevents the protective effect of L-carnitine, indicating that activation of this receptor mediates the protective effect of carnitine. We suggest that the protective effect of carnitine against acute ammonia toxicity in animals is due to the protection against glutamate neurotoxicity according to the above mechanisms.

Regulation of neuronal bioenergy homeostasis by glutamate.
            (Foo et al., 2012)  Download
Bioenergy homeostasis is crucial in maintaining normal cell function and survival and it is thus important to understand cellular mechanisms underlying its regulation. Neurons use a large amount of ATP to maintain membrane potential and synaptic communication, making the brain the most energy consuming organ in the body. Glutamate mediates a large majority of synaptic transmission which is responsible for the expression of neural plasticity and higher brain functions. Most of the energy cost is attributable to the glutamatergic system; under pathological conditions such as stroke and brain ischemia, neural energy depletion is accompanied by a massive release of glutamate. However, the specific cellular processes implicated in glutamate-dependent bioenergy dynamics are not well understood. We find that glutamate induces a rapid and dramatic reduction of ATP levels in neurons, through reduced ATP genesis and elevated consumption. ATP reduction depends on NMDA receptor activity, but is not a result of neuronal firing, gap junction-mediated leaking or intracellular signaling. Similar changes in ATP levels are also induced by synaptic glutamate accumulation following suppression of glutamate transporter activity. Furthermore, the glutamate-induced ATP down-regulation is blocked by the sodium pump inhibitor ouabain, suggesting the sodium pump as the primary energy consumer during glutamate stimulation. These data suggest the important role of glutamate in the control of cellular ATP homeostasis.


 

The blood-brain barrier and glutamate.
            (Hawkins, 2009)  Download
Glutamate concentrations in plasma are 50-100 micromol/L; in whole brain, they are 10,000-12,000 micromol/L but only 0.5-2 micromol/L in extracellular fluids (ECFs). The low ECF concentrations, which are essential for optimal brain function, are maintained by neurons, astrocytes, and the blood-brain barrier (BBB). Cerebral capillary endothelial cells form the BBB that surrounds the entire central nervous system. Tight junctions connect endothelial cells and separate the BBB into luminal and abluminal domains. Molecules entering or leaving the brain thus must pass 2 membranes, and each membrane has distinct properties. Facilitative carriers exist only in luminal membranes, and Na(+)-dependent glutamate cotransporters (excitatory amino acid transporters; EAATs) exist exclusively in abluminal membranes. The EAATs are secondary transporters that couple the Na(+) gradient between the ECF and the endothelial cell to move glutamate against the existing electrochemical gradient. Thus, the EAATs in the abluminal membrane shift glutamate from the ECF to the endothelial cell where glutamate is free to diffuse into blood on facilitative carriers. This organization does not allow net glutamate entry to the brain; rather, it promotes the removal of glutamate and the maintenance of low glutamate concentrations in the ECF. This explains studies that show that the BBB is impermeable to glutamate, even at high concentrations, except in a few small areas that have fenestrated capillaries (circumventricular organs). Recently, the question of whether the BBB becomes permeable in diabetes has arisen. This issue was tested in rats with diet-induced obesity and insulin resistance or with streptozotocin-induced diabetes. Neither condition produced any detectable effect on BBB glutamate transport.

Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium.
            (Kumari et al., 2012)  Download
Glutamate-induced cytotoxicity is partially mediated by enhanced oxidative stress. The objectives of the present study are to determine the effects of glutamate on mitochondrial membrane potential, oxygen consumption, mitochondrial dynamics and autophagy regulating factors and to explore the protective effects of selenium against glutamate cytotoxicity in murine neuronal HT22 cells. Our results demonstrated that glutamate resulted in cell death in a dose-dependent manner and supplementation of 100 nM sodium selenite prevented the detrimental effects of glutamate on cell survival. The glutamate induced cytotoxicity was associated with mitochondrial hyperpolarization, increased ROS production and enhanced oxygen consumption. Selenium reversed these alterations. Furthermore, glutamate increased the levels of mitochondrial fission protein markers pDrp1 and Fis1 and caused increase in mitochondrial fragmentation. Selenium corrected the glutamate-caused mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria. Finally, glutamate activated autophagy markers Beclin 1 and LC3-II, while selenium prevented the activation. These results suggest that glutamate targets the mitochondria and selenium supplementation within physiological concentration is capable of preventing the detrimental effects of glutamate on the mitochondria. Therefore, adequate selenium supplementation may be an efficient strategy to prevent the detrimental glutamate toxicity and further studies are warranted to define the therapeutic potentials of selenium in animal disease models and in human.

Blood glutamate scavenging: insight into neuroprotection.
            (Leibowitz et al., 2012)  Download
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.

Glutamate and Vivian Teichberg: a story about science, medicine, memory and love.
            (Levite Teichberg and Riederer, 2014)  Download
Glutamate is a fascinating molecule, and an extremely important one, due to its numerous effects in the body. Glutamate has many different faces, some unveiled and pretty well known and understood, and some still myste- rious and keep attracting numerous scientists, clinicians, pharmacologists and drug designers from all over the world for dozens of years.


Carnitine prevents NMDA receptor-mediated activation of MAP-kinase and phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture.
            (Llansola and Felipo, 2002)  Download
Activation of N-methyl-D-aspartate (NMDA) receptors leads to increased phosphorylation of the microtubule-associated protein MAP-2 by a mechanism that involves activation of nitric oxide synthase and nitric oxide-induced activation of mitogen-activated protein kinase (MAP-kinase). We have assessed the effects of carnitine on this signal transduction pathway in primary cultures of rat cerebellar neurons. We show that carnitine inhibits NMDA-induced phosphorylation of MAP-2 and that this is due to decreased activation of MAP-kinase. This effect is not due to inhibition by carnitine of NMDA-induced activation of nitric oxide synthase or to quenching of the nitric oxide formed, which are not affected by carnitine. Carnitine also inhibits the increase in phosphorylation of MAP-2 induced by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine, but not nitric oxide-induced activation of soluble guanylate cyclase. These results indicate that carnitine interferes with NMDA-induced, nitric oxide mediated activation of MAP-kinase at a step subsequent to nitric oxide formation.

Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms.
            (Llansola et al., 2002)  Download
Carnitine has beneficial effects in different pathologies and prevents acute ammonia toxicity (ammonia-induced death of animals). Acute ammonia toxicity is mediated by excessive activation of the NMDA-type of glutamate receptors, which mediates glutamate neurotoxicity. We showed that carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons. This supports the idea that the protective effect of carnitine against ammonia toxicity is due to the protective effect against glutamate neurotoxicity. We are studying the mechanism by which carnitine protects against glutamate neurotoxicity. Carnitine increases the binding affinity of glutamate for metabotropic glutamate receptors. The protective effect of carnitine is lost if metabotropic glutamate receptors are blocked with specific antagonists. Moreover, activation of metabotropic glutamate receptors by specific agonists also prevents glutamate neurotoxicity. This indicates that the protective effect of carnitine against glutamate neurotoxicity is mediated by activation of metabotropic glutamate receptors. The molecule of carnitine has a trimethylamine group. Different compounds containing a trimethylamine group (carbachol, betaine, etc.) also prevent ammonia-induced animal death and glutamate-induced neuronal death. Moreover, metabotropic glutamate receptor antagonists also prevent the protective effect of most of these compounds. We summarize here some studies aimed to identify the mechanism and the molecular target that are responsible for the protective effect of carnitine against ammonia and glutamate neurotoxicity. Finally it is also shown that carnitine inhibits the hydrolysis of inositol phospholipids induced by activation of different types of metabotropic receptors, but this effect seems not responsible for its protective effects.

The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling.
            (Mazzoli and Pessione, 2016)  Download
Gut microbiota provides the host with multiple functions (e.g., by contributing to food digestion, vitamin supplementation, and defense against pathogenic strains) and interacts with the host organism through both direct contact (e.g., through surface antigens) and soluble molecules, which are produced by the microbial metabolism. The existence of the so-called gut-brain axis of bi-directional communication between the gastrointestinal tract and the central nervous system (CNS) also supports a communication pathway between the gut microbiota and neural circuits of the host, including the CNS. An increasing body of evidence has shown that gut microbiota is able to modulate gut and brain functions, including the mood, cognitive functions, and behavior of humans. Nonetheless, given the extreme complexity of this communication network, its comprehension is still at its early stage. The present contribution will attempt to provide a state-of-the art description of the mechanisms by which gut microbiota can affect the gut-brain axis and the multiple cellular and molecular communication circuits (i.e., neural, immune, and humoral). In this context, special attention will be paid to the microbial strains that produce bioactive compounds and display ascertained or potential probiotic activity. Several neuroactive molecules (e.g., catecholamines, histamine, serotonin, and trace amines) will be considered, with special focus on Glu and GABA circuits, receptors, and signaling. From the basic science viewpoint, "microbial endocrinology" deals with those theories in which neurochemicals, produced by both multicellular organisms and prokaryotes (e.g., serotonin, GABA, glutamate), are considered as a common shared language that enables interkingdom communication. With regards to its application, research in this area opens the way toward the possibility of the future use of neuroactive molecule-producing probiotics as therapeutic agents for the treatment of neurogastroenteric and/or psychiatric disorders.

Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons.
            (Miñana et al., 1996)  Download
Carnitine prevents acute ammonia toxicity in animals. We propose that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and have shown that carnitine prevents glutamate neurotoxicity. The aim of this work was to assess whether other compounds containing a trimethylamine group are able to prevent ammonia toxicity in mice and/or glutamate toxicity in primary neuronal cultures. It is shown that betaine, trimethylamine-N-oxide, choline, acetylcholine, carbachol and acetylcarnitine prevent ammonia toxicity in mice. They also prevent glutamate but not N-methyl-D-aspartate neurotoxicity. Choline, acetylcholine and acetylcarnitine afford partial (approximately 50%) protection at nanomolar concentrations and nearly complete protection at micromolar concentrations. Trimethylamine-N-oxide, carbachol and betaine afford nearly complete protection at approximately 0.2 mM. The protective effect against glutamate neurotoxicity is prevented by 2-amino-3-phosphonopropionic acid, an antagonist of metabotropic glutamate receptors. Atropine, an antagonist of muscarinic receptors, prevents the protective effect of most of the above compounds against ammonia toxicity in mice and against glutamate toxicity in cultured neurons. These results support the idea that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and that glutamate neurotoxicity could be prevented by activating metabotropic glutamate receptors and/or muscarinic receptors.

Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication.
            (Ruban et al., 2014)  Download
Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure.

Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children.
            (Stanley, 2009)  Download
In addition to its extracellular roles as a neurotransmitter/sensory molecule, glutamate serves important intracellular signaling functions via its metabolism through glutamate dehydrogenase (GDH). GDH is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate in a limited number of tissues in humans, including the liver, the kidney, the brain, and the pancreatic islets. GDH activity is subject to complex regulation by negative (GTP, palmitoyl-coenzyme A) and positive (ADP, leucine) allosteric effectors. This complex regulation allows GDH activity to be modulated by changes in energy state and amino acid availability. The importance of GDH regulation has been highlighted by the discovery of a novel hypoglycemic disorder in children, the hyperinsulinism-hyperammonemia syndrome, which is caused by dominantly expressed, activating mutations of the enzyme that impair its inhibition by GTP. Affected children present in infancy with hypoglycemic seizures after brief periods of fasting or the ingestion of a high-protein meal. Patients have characteristic persistent 3- to 5-fold elevations of blood ammonia concentrations but do not display the usual neurologic symptoms of hyperammonemia. The mutant GDH enzyme shows impaired responses to GTP inhibition. Isolated islets from mice that express the mutant GDH in pancreatic beta cells show an increased rate of glutaminolysis, increased insulin release in response to glutamine, and increased sensitivity to leucine-stimulated insulin secretion. The novel hyperinsulinism-hyperammonemia syndrome indicates that GDH-catalyzed glutamate metabolism plays important roles in 3 tissues: in beta cells, the regulation of amino acid-stimulated insulin secretion; in hepatocytes, the modulation of amino acid catabolism and ammoniagenesis; and in brain neurons, the maintenance of glutamate neurotransmitter concentrations.

 


References

Bobermin, LD, et al. (2012), ‘Resveratrol prevents ammonia toxicity in astroglial cells.’, PLoS One, 7 (12), e52164. PubMed: 23284918
Boyko, M, et al. (2011), ‘Pyruvate’s blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.’, Eur J Neurosci, 34 (9), 1432-41. PubMed: 21936878
Boyko, M, et al. (2014), ‘Brain to blood glutamate scavenging as a novel therapeutic modality: a review.’, J Neural Transm (Vienna), 121 (8), 971-79. PubMed: 24623040
Bravo, JA, et al. (2011), ‘Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.’, Proc Natl Acad Sci U S A, 108 (38), 16050-55. PubMed: 21876150
Burrin, DG and B Stoll (2009), ‘Metabolic fate and function of dietary glutamate in the gut.’, Am J Clin Nutr, 90 (3), 850S-6S. PubMed: 19587091
Felipo, V, et al. (1994a), ‘Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine.’, Adv Exp Med Biol, 368 65-77. PubMed: 7741017
Felipo, V, et al. (1994b), ‘L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity.’, Neurochem Res, 19 (3), 373-77. PubMed: 7909920
Foo, K, L Blumenthal, and HY Man (2012), ‘Regulation of neuronal bioenergy homeostasis by glutamate.’, Neurochem Int, 61 (3), 389-96. PubMed: 22709672
Hawkins, RA (2009), ‘The blood-brain barrier and glutamate.’, Am J Clin Nutr, 90 (3), 867S-74S. PubMed: 19571220
Kumari, S, SL Mehta, and PA Li (2012), ‘Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium.’, PLoS One, 7 (6), e39382. PubMed: 22724008
Leibowitz, A, et al. (2012), ‘Blood glutamate scavenging: insight into neuroprotection.’, Int J Mol Sci, 13 (8), 10041-66. PubMed: 22949847
Levite Teichberg, M and P Riederer (2014), ‘Glutamate and Vivian Teichberg: a story about science, medicine, memory and love.’, J Neural Transm (Vienna), 121 (8), 793-96. PubMed: 25081017
Llansola, M and V Felipo (2002), ‘Carnitine prevents NMDA receptor-mediated activation of MAP-kinase and phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture.’, Brain Res, 947 (1), 50-56. PubMed: 12144852
Llansola, M, et al. (2002), ‘Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms.’, Metab Brain Dis, 17 (4), 389-97. PubMed: 12602515
Mazzoli, R and E Pessione (2016), ‘The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling.’, Front Microbiol, 7 1934. PubMed: 27965654
Miñana, MD, et al. (1996), ‘Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons.’, J Pharmacol Exp Ther, 279 (1), 194-99. PubMed: 8858993
Ruban, A, et al. (2014), ‘Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication.’, J Cereb Blood Flow Metab, 34 (2), 221-27. PubMed: 24149933
Stanley, CA (2009), ‘Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children.’, Am J Clin Nutr, 90 (3), 862S-6S. PubMed: 19625687