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Journal of Neurochemistry Aug 2006Neurons are metabolically handicapped in the sense that they are not able to perform de novo synthesis of neurotransmitter glutamate and gamma-aminobutyric acid (GABA)... (Review)
Review
Neurons are metabolically handicapped in the sense that they are not able to perform de novo synthesis of neurotransmitter glutamate and gamma-aminobutyric acid (GABA) from glucose. A metabolite shuttle known as the glutamate/GABA-glutamine cycle describes the release of neurotransmitter glutamate or GABA from neurons and subsequent uptake into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as neurotransmitter precursor. In this review, the basic properties of the glutamate/GABA-glutamine cycle will be discussed, including aspects of transport and metabolism. Discussions of stoichiometry, the relative role of glutamate vs. GABA and pathological conditions affecting the glutamate/GABA-glutamine cycling are presented. Furthermore, a section is devoted to the accompanying ammonia homeostasis of the glutamate/GABA-glutamine cycle, examining the possible means of intercellular transfer of ammonia produced in neurons (when glutamine is deamidated to glutamate) and utilized in astrocytes (for amidation of glutamate) when the glutamate/GABA-glutamine cycle is operating. A main objective of this review is to endorse the view that the glutamate/GABA-glutamine cycle must be seen as a bi-directional transfer of not only carbon units but also nitrogen units.
Topics: Ammonia; Animals; Biological Transport; Glutamic Acid; Glutamine; Homeostasis; Humans; gamma-Aminobutyric Acid
PubMed: 16787421
DOI: 10.1111/j.1471-4159.2006.03913.x -
Neurology Apr 2019To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available.
METHODS
This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT.
RESULTS
All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure.
CONCLUSION
These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.
Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Double-Blind Method; Female; Glutamates; Glutamic Acid; Humans; Rett Syndrome; Treatment Outcome
PubMed: 30918097
DOI: 10.1212/WNL.0000000000007316 -
Annals of Nutrition & Metabolism 2018The 2018 Dietary Glutamate Workshop was organized and sponsored by the International Glutamate Technical Committee to provide a platform for a broad expert discussion on...
The 2018 Dietary Glutamate Workshop was organized and sponsored by the International Glutamate Technical Committee to provide a platform for a broad expert discussion on all relevant aspects of glutamate metabolism and safety in human nutrition. The participants reached a consensus with previous safety evaluations conducted by the global expert bodies, but contradicted the 2017 re-evaluation of dietary glutamates by the European Food Safety Authority, which proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight per day. The participants of the Workshop concluded that the present knowledge on metabolism, kinetics, developmental and general toxicity of dietary glutamates did not warrant a change in the previous ADI of "not specified."
Topics: Congresses as Topic; Diet; Food Additives; Food Safety; Glutamic Acid; Humans; No-Observed-Adverse-Effect Level
PubMed: 30508812
DOI: 10.1159/000494775 -
Journal of Neural Transmission (Vienna,... Aug 2014Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that... (Review)
Review
Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways on the other. It exerts its action through a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated previously in a broad spectrum of acute and chronic neurodegenerative diseases. In this review, we discuss existing data on the role of glutamate as a growth factor for neoplastic cells, the expression of glutamate receptors in various types of benign and malignant neoplasms, and the potential roles that GluRs play in cancer development and progression along with their clinical significance. We conclude that glutamate-related receptors and their signaling pathways may provide novel therapeutic opportunities for a variety of malignant human diseases.
Topics: Animals; Glutamic Acid; Humans; Neoplasms; Receptors, Glutamate
PubMed: 24610491
DOI: 10.1007/s00702-014-1182-6 -
Annals of Nutrition & Metabolism 2018Re-evaluation of the use of glutamic acid and glutamate salts (referred to as glutamate hereafter) by the European Food Safety Authority (EFSA) proposed a group... (Review)
Review
BACKGROUND
Re-evaluation of the use of glutamic acid and glutamate salts (referred to as glutamate hereafter) by the European Food Safety Authority (EFSA) proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight (bw)/day.
SUMMARY
This ADI is below the normal dietary intake, while even intake of free glutamate by breast-fed babies can be above this ADI. In addition, the pre-natal developmental toxicity study selected by EFSA, has never been used by regulatory authorities worldwide for the safety assessment of glutamate despite it being available for nearly 40 years. Also, the EFSA ignored that toxicokinetic data provide support for eliminating the use of an uncertainty factor for interspecies differences in kinetics. Key Messages: A 3-generation reproductive toxicity study in mice that includes extensive brain histopathology, provides a better point of departure showing no effects up to the highest dose tested of 6,000 mg/kg bw/day. Furthermore, kinetic data support use of a compound-specific uncertainty factor of 25 instead of 100. Thus, an ADI of at least 240 mg/kg bw/day would be indicated. In fact, there is no compelling evidence to indicate that the previous ADI of "not specified" warrants any change.
Topics: Animals; Food Additives; Glutamic Acid; Humans; Mice; No-Observed-Adverse-Effect Level; Rats; Risk Assessment; Toxicokinetics
PubMed: 30508819
DOI: 10.1159/000494783 -
ELife May 2022Fluorescent glutamate sensors shed light on the microscopic organization underlining spontaneous neurotransmission.
Fluorescent glutamate sensors shed light on the microscopic organization underlining spontaneous neurotransmission.
Topics: Glutamic Acid; Synapses; Synaptic Transmission
PubMed: 35608410
DOI: 10.7554/eLife.79446 -
Annals of Nutrition & Metabolism 2018Glutamate is a non-essential amino acid at the crossroads of nitrogen and energy metabolism. Glutamate metabolism is characterized by reactions that may be anabolic or... (Review)
Review
BACKGROUND
Glutamate is a non-essential amino acid at the crossroads of nitrogen and energy metabolism. Glutamate metabolism is characterized by reactions that may be anabolic or catabolic in nature depending on the tissue (i.e., glutamate dehydrogenase, transaminases), and it can also be either the precursor or the metabolite of glutamine. Unlike glutamine, which is the form of interorgan ammonia transport, glutamate metabolism is mostly compartmentalized within the cells, its interorgan exchanges being limited to a flux from liver to muscle.
SUMMARY
Glutamate catabolism is extremely intense in the splanchnic area, such that after a meal (rich in proteins) almost no glutamate appears in the systemic circulation. However, this process is saturable as after glutamate loading at a high dose level, glutamate appears dose-dependently in the circulation. This systemic glutamate -appearance is blunted if glutamate is co-ingested with a carbohydrate source. Key Messages: The underlying reason for this highly specific metabolism is that glutamate plays a key role in nitrogen homeostasis, and the organism does all it can to limit the bioavailability of glutamate, which can be neurotoxic in excess. As glutamate is never eaten alone, its bioavailability will be limited if not negligible, and no adverse effects are to be expected in adult humans.
Topics: Adult; Animals; Diet; Glutamate Decarboxylase; Glutamate Dehydrogenase; Glutamic Acid; Humans; Liver; Muscles
PubMed: 30508813
DOI: 10.1159/000494776 -
Journal of Clinical Sleep Medicine :... Mar 2021Ortega-Albás JJ, López R, Martínez A, Carratalá S, Echeverria I, Ortega P. Kleine-Levin syndrome, GABA, and glutamate. . 2021;17(3):609–610.
Ortega-Albás JJ, López R, Martínez A, Carratalá S, Echeverria I, Ortega P. Kleine-Levin syndrome, GABA, and glutamate. . 2021;17(3):609–610.
Topics: Glutamic Acid; Humans; Kleine-Levin Syndrome; gamma-Aminobutyric Acid
PubMed: 33283755
DOI: 10.5664/jcsm.9058 -
Scientific Reports Jul 2020Glutamate (Glu), the key excitatory neurotransmitter in the central nervous system, is considered essential for brain functioning and has a vital role in learning and...
Glutamate (Glu), the key excitatory neurotransmitter in the central nervous system, is considered essential for brain functioning and has a vital role in learning and memory formation. Earlier it was considered as a harmful agent but later found to be useful for many body functions. However, studies regarding the effects of free L-Glu administration on CNS function are limited. Therefore, current experiment is aimed to monitor the neurobiological effects of free L-Glu in male rats. L-Glu was orally administered to rats for 5-weeks and changes in behavioral performance were monitored. Thereafter, brain and hippocampus were collected for oxidative and neurochemical analysis. Results showed that chronic supplementation of free L-Glu enhanced locomotor performance and cognitive function of animals which may be attributed to the improved antioxidant status and cholinergic, monoaminergic and glutamatergic neurotransmission in brain and hippocampus. Current results showed that chronic supplementation of L-Glu affects the animal behaviour and brain functioning via improving the neurochemical and redox system of brain. Free L-Glu could be a useful therapeutic agent to combat neurological disturbances however this requires further targeted studies.
Topics: Administration, Oral; Animals; Behavior, Animal; Brain Chemistry; Dietary Supplements; Glutamic Acid; Hippocampus; Locomotion; Male; Memory; Models, Animal; Oxidation-Reduction; Rats; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 32641780
DOI: 10.1038/s41598-020-68041-y -
Progress in Neurobiology Apr 1996Bioenergetic defects and abnormalities in glutamate neurotransmission have both been proposed to play important roles in neurological diseases of varying chronology,... (Review)
Review
Bioenergetic defects and abnormalities in glutamate neurotransmission have both been proposed to play important roles in neurological diseases of varying chronology, etiology and pathology. Recent experimental evidence suggests an intimate relationship between these two systems. Metabolic inhibition predisposes neurons to glutamate-mediated "excitotoxic" damage. The exact mechanism of this increased susceptibility is yet to be defined, but may involve, singly or in combination, decreased voltage-dependent Mg2+ blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, abnormalities in cellular Ca2+ homeostasis, or elevated production of reactive oxygen species. It is believed that enhancement of excitotoxicity by impaired metabolism may be a ubiquitous mechanism of neuronal death in neurological disease. Further elucidation of the exact mechanism of this enhancement may lead to the discovery of new targets for therapeutic intervention.
Topics: Animals; Energy Metabolism; Excitatory Amino Acids; Glutamic Acid; Humans; Neurotransmitter Agents
PubMed: 8809910
DOI: 10.1016/0301-0082(96)00006-8