N-Methyl D-Aspartic Acid (NMDA Receptors and Depression

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Enver Yusuf Sivrioglu

2009-06-01

Full Text Available The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more

Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials.

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Lee, Mei-Yi; Lin, Yi-Ruu; Tu, Yi-Shu; Tseng, Yufeng Jane; Chan, Ming-Huan; Chen, Hwei-Hsien

2017-02-28

Sarcosine, a glycine transporter type 1 inhibitor and an N-methyl-D-aspartate (NMDA) receptor co-agonist at the glycine binding site, potentiates NMDA receptor function. Structurally similar to sarcosine, N,N-dimethylglycine (DMG) is also N-methyl glycine-derivative amino acid and commonly used as a dietary supplement. The present study compared the effects of sarcosine and DMG on NMDA receptor-mediated excitatory field potentials (EFPs) in mouse medial prefrontal cortex brain slices using a multi-electrode array system. Glycine, sarcosine and DMG alone did not alter the NMDA receptor-mediated EFPs, but in combination with glutamate, glycine and its N-methyl derivatives significantly increased the frequency and amplitude of EFPs. The enhancing effects of glycine analogs in combination with glutamate on EFPs were remarkably reduced by the glycine binding site antagonist 7-chlorokynurenate (7-CK). However, DMG, but not sarcosine, reduced the frequency and amplitude of EFPs elicited by co-application of glutamate plus glycine. D-cycloserine, a partial agonist at the glycine binding site on NMDA receptors, affected EFPs in a similar manner to DMG. Furthermore, DMG, but not sarcosine, reduced the frequencies and amplitudes of EFPs elicited by glutamate plus D-serine, another endogenous ligand for glycine binding site. These findings suggest that sarcosine acts as a full agonist, yet DMG is a partial agonist at glycine binding site of NMDA receptors. The molecular docking analysis indicated that the interactions of glycine, sarcosine, and DMG to NMDA receptors are highly similar, supporting that the glycine binding site of NMDA receptors is a critical target site for sarcosine and DMG.

Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids

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Conti, Paola; De Amici, Marco; Grazioso, Giovanni

2005-01-01

stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid (+)-2, (-)-2, (+)-3, and (-)-3 were tested at ionotropic and metabotropic glutamate receptor subtypes. The most potent NMDA receptor antagonists [(+)-2, (-)-4, and (+)-5] showed a significant......The four stereoisomers of 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four...

Intracellular synthesis of glutamic acid in Bacillus methylotrophicus SK19.001, a glutamate-independent poly(γ-glutamic acid)-producing strain.

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Peng, Yingyun; Zhang, Tao; Mu, Wanmeng; Miao, Ming; Jiang, Bo

2016-01-15

Bacillus methylotrophicus SK19.001 is a glutamate-independent strain that produces poly(γ-glutamic acid) (γ-PGA), a polymer of D- and L-glutamic acids that possesses applications in food, the environment, agriculture, etc. This study was undertaken to explore the synthetic pathway of intracellular L- and D-glutamic acid in SK19.001 by investigating the effects of tricarboxylic acid cycle intermediates and different amino acids as metabolic precursors on the production of γ-PGA and analyzing the activities of the enzymes involved in the synthesis of L- and D-glutamate. Tricarboxylic acid cycle intermediates and amino acids could participate in the synthesis of γ-PGA via independent pathways in SK19.001. L-Aspartate aminotransferase, L-glutaminase and L-glutamate synthase were the enzymatic sources of L-glutamate. Glutamate racemase was responsible for the formation of D-glutamate for the synthesis of γ-PGA, and the synthetase had stereoselectivity for glutamate substrate. The enzymatic sources of L-glutamate were investigated for the first time in the glutamate-independent γ-PGA-producing strain, and multiple enzymatic sources of L-glutamate were verified in SK19.001, which will benefit efforts to improve production of γ-PGA with metabolic engineering strategies. © 2015 Society of Chemical Industry.

Effect of the non-NMDA receptor antagonist GYKI 52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia.

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Arvin, B; Lekieffre, D; Graham, J L; Moncada, C; Chapman, A G; Meldrum, B S

1994-04-01

The effect of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) on ischaemia-induced changes in the microdialysate and tissue concentrations of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was studied in rats. Twenty minutes of four-vessel occlusion resulted in a transient increase in microdialysate levels of glutamate, aspartate, and GABA in striatum, cortex, and hippocampus. Administration of GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min intravenously starting 20 min before onset of ischaemia) inhibited ischaemia-induced increases in microdialysate glutamate and GABA in striatum without affecting the increases in hippocampus or cortex. Twenty minutes of four-vessel occlusion resulted in immediate small decreases and larger delayed (72 h) decreases in tissue levels of glutamate and aspartate. Transient increases in tissue levels of GABA were shown in all three structures at the end of the ischaemic period. At 72 h, after the ischaemic period, significantly reduced GABA levels were observed in striatum and hippocampus. GYKI 52466, given under identical conditions as above, augmented the ischaemia-induced decrease in striatal tissue levels of glutamate and aspartate, without significantly affecting the decreases in hippocampus and cortex. Twenty minutes of ischaemia resulted in a large increase in microdialysate dopamine in striatum. GYKI 52466 failed to inhibit this increase. Kainic acid (500 microM infused through the probe for 20 min) caused increases in microdialysate glutamate and aspartate in the striatum. GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min) completely inhibited the kainic acid-induced glutamate release. In conclusion, the action of the non-NMDA antagonist, GYKI 52466, in the striatum is different from that in the cortex and hippocampus. The inhibition by GYKI 52466 of ischaemia-induced and kainate-induced increases in microdialysate

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

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Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

2017-04-14

Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.

MDMA Decreases Gluatamic Acid Decarboxylase (GAD) 67-Immunoreactive Neurons in the Hippocampus and Increases Seizure Susceptibility: Role for Glutamate

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Huff, Courtney L.; Morano, Rachel L.; Herman, James P.; Yamamoto, Bryan K.; Gudelsky, Gary A.

2016-01-01

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37–58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30 days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures. PMID:27773601

NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes.

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Lalo, Ulyana; Pankratov, Yuri; Kirchhoff, Frank; North, R Alan; Verkhratsky, Alexei

2006-03-08

Chemical transmission between neurons and glial cells is an important element of integration in the CNS. Here, we describe currents activated by NMDA in cortical astrocytes, identified in transgenic mice that express enhanced green fluorescent protein under control of the human glial fibrillary acidic protein promoter. Astrocytes were studied by whole-cell voltage clamp either in slices or after gentle nonenzymatic mechanical dissociation. Acutely isolated astrocytes showed a three-component response to glutamate. The initial rapid component was blocked by 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), which is an antagonist of AMPA receptors (IC50, 2 microM), and the NMDA receptor antagonist D-AP-5 blocked the later sustained component (IC50, 0.6 microM). The third component of glutamate application response was sensitive to D,L-threo-beta-benzyloxyaspartate, a glutamate transporter blocker. Fast application of NMDA evoked concentration-dependent inward currents (EC50, 0.3 microM); these showed use-dependent block by (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801). These NMDA-evoked currents were linearly dependent on membrane potential and were not affected by extracellular magnesium at concentrations up to 10 mM. Electrical stimulation of axons in layer IV-VI induced a complex inward current in astrocytes situated in the cortical layer II, part of which was sensitive to MK-801 at holding potential -80 mV and was not affected by the AMPA glutamate receptor antagonist NBQX. The fast miniature spontaneous currents were observed in cortical astrocytes in slices as well. These currents exhibited both AMPA and NMDA receptor-mediated components. We conclude that cortical astrocytes express functional NMDA receptors that are devoid of Mg2+ block, and these receptors are involved in neuronal-glial signal transmission.

Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

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Paes, Paulo Cesar de Arruda

2002-07-01

The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake.

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Stanley, B G; Urstadt, K R; Charles, J R; Kee, T

2011-07-25

By the 1990s a convergence of evidence had accumulated to suggest that neurons within the lateral hypothalamus (LH) play important roles in the stimulation of feeding behavior. However, there was little direct evidence demonstrating that neurotransmitters in the LH could, like electrical stimulation, elicit feeding in satiated animals. The present paper is a brief review in honor of Bartley Hoebel's scientific contributions, emphasizing the evidence from my lab that the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in the LH mediate feeding stimulation and feeding inhibition respectively. Specifically, we summarize evidence that LH injection of glutamate, or agonists of its N-methyl-D-aspartate (NMDA) and non-NMDA receptors, elicits feeding in satiated rats, that NMDA receptor antagonists block the eating elicited by NMDA and, more importantly, that NMDA blockade suppresses natural feeding and can reduce body weight. Conversely, GABA(A) agonists injected into the LH suppress feeding and can also reduce body weight, while GABA(A) receptor antagonists actually elicit eating when injected into the LH of satiated rats. It is suggested that natural feeding may reflect the moment-to-moment balance in the activity of glutamate and GABA within the LH. Copyright © 2011 Elsevier Inc. All rights reserved.

Synergy by secretory phospholipase A2 and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures

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Kolko, M; DeCoster, M A; de Turco, E B

1996-01-01

glutamate and sPLA2 from bee venom. sPLA2, at concentrations eliciting low neurotoxicity (acid into triacylglycerols. Free [3H]arachidonic acid accumulated at higher enzyme concentrations......, from Taipan snake venom. The NMDA receptor antagonist MK-801 blocked glutamate effects and partially inhibited sPLA2 OS2 but not sPLA2 from bee venom-induced arachidonic acid release. Thus, the synergy with glutamate and very low concentrations of exogenously added sPLA2 suggests a potential role......Secretory and cytosolic phospholipases A2 (sPLA2 and cPLA2) may contribute to the release of arachidonic acid and other bioactive lipids, which are modulators of synaptic function. In primary cortical neuron cultures, neurotoxic cell death and [3H]arachidonate metabolism was studied after adding...

Glutamatergic induction of CREB phosphorylation and Fos expression in primary cultures of the suprachiasmatic hypothalamus in vitro is mediated by co-ordinate activity of NMDA and non-NMDA receptors.

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Schurov, I L; McNulty, S; Best, J D; Sloper, P J; Hastings, M H

1999-01-01

Exposure of Syrian hamsters to light 1 h after lights-off rapidly (10 min) induced nuclear immunoreactivity (-ir) to the phospho-Ser133 form of the Ca2+/cAMP response element (CRE) binding protein (pCREB) in the retinorecipient zone of the suprachiasmatic nuclei (SCN). Light also induced nuclear Fos-ir in the same region of the SCN after 1 h. The glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker MK801 attenuated the photic induction of both factors. To investigate glutamatergic regulation of pCREB and Fos further, tissue blocks and primary cultures of neonatal hamster SCN were examined by Western blotting and immunocytochemistry in vitro. On Western blots of SCN tissue, the pCREB-ir signal at 45 kDa was enhanced by glutamate or a mixture of glutamatergic agonists (NMDA, amino-methyl proprionic acid (AMPA), and Kainate (KA)), whereas total CREB did not change. Glutamate or the mixture of agonists also induced a 56 kDa band identified as Fos protein in SCN tissue. In dissociated cultures of SCN, glutamate caused a rapid (15 min) induction of nuclear pCREB-ir and Fos-ir (after 60 min) exclusively in neurones, both GABA-ir and others. Treatment with NMDA alone had no effect on pCREB-ir. AMPA alone caused a slight increase in pCREB-ir. However, kainate alone or in combination with NMDA and AMPA induced nuclear pCREB-ir equal to that induced by glutamate. The effects of glutamate on pCREB-ir and Fos-ir were blocked by antagonists of both NMDA (MK801) and AMPA/KA (NBQX) receptors. In the absence of extracellular Mg2+, MK801 blocked glutamatergic induction of Fos-ir. However, the AMPA/KA receptor antagonist was no longer effective at blocking glutamatergic induction of either Fos-ir or pCREB-ir, consistent with the model that glutamate regulates gene expression in the SCN by a co-ordinate action through both NMDA and AMPA/KA receptors. Glutamatergic induction of nuclear pCREB-ir in GABA-ir neurones was blocked by KN-62 an inhibitor of Ca2+/Calmodulin (Ca

Glutamic acid as anticancer agent: An overview.

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Dutta, Satyajit; Ray, Supratim; Nagarajan, K

2013-10-01

The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed.

α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model.

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Jung, Kyoung In; Kim, Jie Hyun; Park, Chan Kee

2015-10-15

Excitotoxicity, glutamate-induced toxic effects to retinal ganglion cells (RGCs), is one of several mechanisms of RGC loss suggested in glaucoma. In this study, we focused on the role of glutamate transporter of glial cells as well as N-methyl-d-aspartate (NMDA) receptor with regard to glutamate toxicity in glaucoma. We also investigated whether α2-adrenoceptor activation could modulate glutamate transporters and NMDA receptors in a chronic ocular hypertension model. Brimonidine 0.15% was administered topically to the eyes of experimental glaucoma and control animals twice daily. After 8 weeks of intraocular pressure (IOP) elevation, staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) revealed an increase in the ganglion cell layer, and the number of TUNEL-positive cells was reduced by brimonidine treatment (P<0.05). Animals with experimentally induced glaucoma exhibited an increase in retinal stress marker glial fibrillary acidic protein (GFAP) immunoreactivity; brimonidine treatment reduced GFAP. Excitatory amino acid transporter 1(EAAT1) expression remained stable throughout the period of chronic ocular hypertension. α2-Adrenergic treatment upregulated EAAT1 protein levels (P<0.05). NMDA receptor (GluN1) expression was stimulated by chronic elevation of IOP, and GluN1-positive cells in ganglion cell layer were co-localized with TUNEL staining. Brimonidine administration suppressed GluN1 levels (P<0.05). These results indicate that brimonidine decreased RGC apoptosis, upregulating EAAT1 and downregulating NMDA receptors. We suggest that topical brimonidine treatment may decrease the glutamate excitotoxicity through modulation of glutamate transporter and NMDA receptor in glaucoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus

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Rania M. Khalil

2016-08-01

Full Text Available Background: Monosodium glutamate (MSG is a flavor enhancer used in food industries. MSG is well documented to induce neurotoxicity. Curcumin (CUR reportedly possesses beneficial effects against various neurotoxic insults. Hence, this present study has been designed to evaluate the neuroprotective effect of curcumin on MSG-induced neurotoxicity in rats. Methods: Thirty-two male Wister rats were divided into four groups (n=8: Control group, MSG group, CUR group and MSG + CUR group. CUR (Curcumin 150 mg/kg, orally was given day after day for four weeks along with MSG (4 mg/kg, orally. After 4 weeks, rats were sacrificed and brain hippocampus was isolated immediately on ice. Inflammatory marker TNFα and acetylcholinesterase (AChE activity (marker for cholinergic function were estimated. Gene expressions of metabotropic glutamate receptor 5 (mGluR5 and N-methyl-D-aspartate receptor 2B (NMDA2B along with glutamate concentration were assessed. Results: Treatment with CUR significantly attenuated AChE activity and TNFα in MSG-treated animals. The anti-inflammatory properties of CUR may be responsible for this observed neuroprotective action. A possible role of CUR to attenuate both glutamate level and gene expression of NMDA2B and mGLUR5 in brain hippocampus was established when compared to MSG group. Conclusion: We concluded that CUR as flavor enhancer protects against MSG-induced neurotoxicity in rats.

The Degradation of 14C-Glutamic Acid by L-Glutamic Acid Decarboxylase.

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Dougherty, Charles M; Dayan, Jean

1982-01-01

Describes procedures and semi-micro reaction apparatus (carbon dioxide trap) to demonstrate how a particular enzyme (L-Glutamic acid decarboxylase) may be used to determine the site or sites of labeling in its substrate (carbon-14 labeled glutamic acid). Includes calculations, solutions, and reagents used. (Author/SK)

Involvement of NMDA receptor in low-frequency magnetic field-induced anxiety in mice.

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Salunke, Balwant P; Umathe, Sudhir N; Chavan, Jagatpalsingh G

2014-12-01

It had been reported that exposure to extremely low-frequency magnetic field (ELFMF) induces anxiety in human and rodents. Anxiety mediates via the activation of N-methyl-d-aspartate (NMDA) receptor, whereas activation of γ-aminobutyric acid (GABA) receptor attenuates the same. Hence, the present study was carried out to understand the contribution of NMDA and/or GABA receptors modulation in ELFMF-induced anxiety for which Swiss albino mice were exposed to ELFMF (50 Hz, 10 G) by subjecting them to Helmholtz coils. The exposure was for 8 h/day for 7, 30, 60, 90 and 120 days. Anxiety level was assessed in elevated plus maze, open field test and social interaction test, on 7th, 30th, 60th, 90th and 120th exposure day, respectively. Moreover, the role of GABA and glutamate in ELFMF-induced anxiety was assessed by treating mice with muscimol [0.25 mg/kg intraperitoneally (i.p.)], bicuculline (1.0 mg/kg i.p.), NMDA (15 mg/kg i.p.) and MK-801 (0.03 mg/kg i.p.), as a GABAA and NMDA receptor agonist and antagonist, respectively. Glutamate receptor agonist exacerbated while inhibitor attenuated the ELFMF-induced anxiety. In addition, levels of GABA and glutamate were determined in regions of the brain viz, cortex, striatum, hippocampus and hypothalamus. Experiments demonstrated significant elevation of GABA and glutamate levels in the hippocampus and hypothalamus. However, GABA receptor modulators did not produce significant effect on ELFMF-induced anxiety and elevated levels of GABA at tested dose. Together, these findings suggest that ELFMF significantly induced anxiety behavior, and indicated the involvement of NMDA receptor in its effect.

Glutamic acid as anticancer agent: An overview

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Dutta, Satyajit; Ray, Supratim; Nagarajan, K.

2013-01-01

The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. I...

NMDA Receptor Modulators in the Treatment of Drug Addiction.

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Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

2013-02-06

Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

NMDA Receptor Modulators in the Treatment of Drug Addiction

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M. Foster Olive

2013-02-01

Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

Glutamate as a neurotransmitter in the brain: review of physiology and pathology.

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Meldrum, B S

2000-04-01

Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.

Molecular pharmacology of human NMDA receptors

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Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

2012-01-01

N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical ani...

Effects of a NR2B Selective NMDA Glutamate Antagonist, CP-101,606, on Dyskinesia and Parkinsonism

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Nutt, John G.; Gunzler, Steven A; Kirchhoff, Trish; Hogarth, Penelope; Weaver, Jerry L.; Krams, Michael; Jamerson, Brenda; Menniti, Frank S.; Landen, Jaren W.

2011-01-01

Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson’s disease (PD). In a randomized, double-blind, placebo-controlled clinical trial we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP-101,606, on the response to two-hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP-101,606 reduced the maximum severity of levodopa-induced dyskinesia approximately 30% but neither dose improved parkinsonism. CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects. PMID:18759356

Enzymatic production of α-ketoglutaric acid from l-glutamic acid via l-glutamate oxidase.

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Niu, Panqing; Dong, Xiaoxiang; Wang, Yuancai; Liu, Liming

2014-06-10

In this study, a novel strategy for α-ketoglutaric acid (α-KG) production from l-glutamic acid using recombinant l-glutamate oxidase (LGOX) was developed. First, by analyzing the molecular structure characteristics of l-glutamic acid and α-KG, LGOX was found to be the best catalyst for oxidizing the amino group of l-glutamic acid to a ketonic group without the need for exogenous cofactor. Then the LGOX gene was expressed in Escherichia coli BL21 (DE3) in a soluble and active form, and the recombinant LGOX activity reached to a maximum value of 0.59U/mL at pH 6.5, 30°C. Finally, the maximum α-KG concentration reached 104.7g/L from 110g/L l-glutamic acid in 24h, under the following optimum conditions: 1.5U/mL LGOX, 250U/mL catalase, 3mM MnCl2, 30°C, and pH 6.5. Copyright © 2014. Published by Elsevier B.V.

The application of glutamic acid alpha-decarboxylase for the valorization of glutamic acid

NARCIS (Netherlands)

Lammens, T.M.; Biase, De Daniela; Franssen, M.C.R.; Scott, E.L.; Sanders, J.P.M.

2009-01-01

Glutamic acid is an important constituent of waste streams from biofuels production. It is an interesting starting material for the synthesis of nitrogen containing bulk chemicals, thereby decreasing the dependency on fossil fuels. On the pathway from glutamic acid to a range of molecules, the

Microbial production of poly-γ-glutamic acid.

Science.gov (United States)

Sirisansaneeyakul, Sarote; Cao, Mingfeng; Kongklom, Nuttawut; Chuensangjun, Chaniga; Shi, Zhongping; Chisti, Yusuf

2017-09-05

Poly-γ-glutamic acid (γ-PGA) is a natural, biodegradable and water-soluble biopolymer of glutamic acid. This review is focused on nonrecombinant microbial production of γ-PGA via fermentation processes. In view of its commercial importance, the emphasis is on L-glutamic acid independent producers (i.e. microorganisms that do not require feeding with the relatively expensive amino acid L-glutamic acid to produce γ-PGA), but glutamic acid dependent production is discussed for comparison. Strategies for improving production, reducing costs and using renewable feedstocks are discussed.

21 CFR 182.1045 - Glutamic acid.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glutamic acid. 182.1045 Section 182.1045 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN....1045 Glutamic acid. (a) Product. Glutamic acid. (b) [Reserved] (c) Limitations, restrictions, or...

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

Science.gov (United States)

Levite, Mia

2014-08-01

Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti-glutamate

Glutamate dehydrogenase (RocG) in Bacillus licheniformis WX-02: Enzymatic properties and specific functions in glutamic acid synthesis for poly-γ-glutamic acid production.

Science.gov (United States)

Tian, Guangming; Wang, Qin; Wei, Xuetuan; Ma, Xin; Chen, Shouwen

2017-04-01

Poly-γ-glutamic acid (γ-PGA), a natural biopolymer, is widely used in cosmetics, medicine, food, water treatment, and agriculture owing to its features of moisture sequestration, cation chelation, non-toxicity and biodegradability. Intracellular glutamic acid, the substrate of γ-PGA, is a limiting factor for high yield in γ-PGA production. Bacillus subtilis and Bacillus licheniformis are both important γ-PGA producing strains, and B. subtilis synthesizes glutamic acid in vivo using the unique GOGAT/GS pathway. However, little is known about the glutamate synthesis pathway in B. licheniformis. The aim of this work was to characterize the glutamate dehydrogenase (RocG) in glutamic acid synthesis from B. licheniformis with both in vivo and in vitro experiments. By re-directing the carbon flux distribution, the rocG gene deletion mutant WX-02ΔrocG produced intracellular glutamic acid with a concentration of 90ng/log(CFU), which was only 23.7% that of the wild-type WX-02 (380ng/log(CFU)). Furthermore, the γ-PGA yield of mutant WX-02ΔrocG was 5.37g/L, a decrease of 45.3% compared to the wild type (9.82g/L). In vitro enzymatic assays of RocG showed that RocG has higher affinity for 2-oxoglutarate than glutamate, and the glutamate synthesis rate was far above degradation. This is probably the first study to reveal the glutamic acid synthesis pathway and the specific functions of RocG in B. licheniformis. The results indicate that γ-PGA production can be enhanced through improving intracellular glutamic acid synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

DEFF Research Database (Denmark)

Madsen, U; Bräuner-Osborne, H; Frydenvang, Karla Andrea

2001-01-01

Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (i......GluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown...... to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments...

The role of striatal NMDA receptors in drug addiction.

Science.gov (United States)

Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

2009-01-01

The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

Irreversible amnesia in rats and edible snails under conditions of associative memory reconsolidation disturbance caused by NMDA-glutamate receptor antagonist.

Science.gov (United States)

Storozheva, Z I; Solntseva, S V; Nikitin, V P; Proshin, A T; Sherstnev, V V

2011-01-01

The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory.

A Glutamic Acid-Producing Lactic Acid Bacteria Isolated from Malaysian Fermented Foods

Science.gov (United States)

Zareian, Mohsen; Ebrahimpour, Afshin; Bakar, Fatimah Abu; Mohamed, Abdul Karim Sabo; Forghani, Bita; Ab-Kadir, Mohd Safuan B.; Saari, Nazamid

2012-01-01

l-glutamaic acid is the principal excitatory neurotransmitter in the brain and an important intermediate in metabolism. In the present study, lactic acid bacteria (218) were isolated from six different fermented foods as potent sources of glutamic acid producers. The presumptive bacteria were tested for their ability to synthesize glutamic acid. Out of the 35 strains showing this capability, strain MNZ was determined as the highest glutamic-acid producer. Identification tests including 16S rRNA gene sequencing and sugar assimilation ability identified the strain MNZ as Lactobacillus plantarum. The characteristics of this microorganism related to its glutamic acid-producing ability, growth rate, glucose consumption and pH profile were studied. Results revealed that glutamic acid was formed inside the cell and excreted into the extracellular medium. Glutamic acid production was found to be growth-associated and glucose significantly enhanced glutamic acid production (1.032 mmol/L) compared to other carbon sources. A concentration of 0.7% ammonium nitrate as a nitrogen source effectively enhanced glutamic acid production. To the best of our knowledge this is the first report of glutamic acid production by lactic acid bacteria. The results of this study can be further applied for developing functional foods enriched in glutamic acid and subsequently γ-amino butyric acid (GABA) as a bioactive compound. PMID:22754309

D-aspartate and NMDA, but not L-aspartate, block AMPA receptors in rat hippocampal neurons

DEFF Research Database (Denmark)

Gong, Xiang-Qun; Frandsen, Anne; Lu, Wei-Yang

2005-01-01

1 The amino acid, D-aspartate, exists in the mammalian brain and is an agonist at the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors. Here, for the first time, we studied the actions of D-aspartate on alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs......) in acutely isolated rat hippocampal neurons. 2 In the presence of the NMDA receptor channel blocker, MK801, D-aspartate inhibited kainate-induced AMPAR current in hippocampal neurons. The inhibitory action of D-aspartate on kainate-induced AMPAR current was concentration-dependent and was voltage......-independent in the tested voltage range (-80 to +60 mV). 3 The estimated EC50 of the L-glutamate-induced AMPAR current was increased in the presence of D-aspartate, while the estimated maximum L-glutamate-induced AMPAR current was not changed. D-aspartate concentration-dependently shifted the dose-response curve of kainate...

Influence of the glutamic acid content of the diet on the catabolic rate of labelled glutamic acid in rats. 3

International Nuclear Information System (INIS)

Simon, O.; Wilke, A.; Bergner, H.

1984-01-01

Mal rats received during a 8 days experimental feeding period diets with different contents in glutamic acid. The daily feed intake was restricted to the energy maintenance level of 460 kJ/kg/sup 0.75/. The diet contained a mixture of L-amino acids corresponding to the pattern of egg protein except glutamic acid. Glutamic acid was added successively at 10 levels (0 to 14.8 % of dry matter) and the resulting diets were fed to groups of 4 animals each. At the end of the experimental feeding period 14 C- and 15 N-labelled glutamic acid were applied by intragastric infusion. CO 2 and 14 CO 2 excretion was measured during the following 4 hours and the urinary N and 15 N excretion during the following 24 hours. The CO 2 excretion decreased from 53 to 44 mmol CO 2 /100g body weight with increasing levels of dietary glutamic acid. This change seems to result from the increasing proportion of amino acids as an energetic fuel. While the amount of oxidized glutamic acid increased with increasing supplements of glutamic acid the relative 14 CO 2 excretion decreased from 57 to 48 % of the applied radioactivity. The urinary 15 N excretion during 24 hours was 31 % of the given amount of 15 N if no glutamic acid was included in the diet. This proportion increased successively up to 52 % in the case of the highest supply of glutamic acid. Because the total N excretion increased at the same extent as the 15 N excretion a complete mixing of the NH 2 groups resulting from glutamic acid due to desamination with the ammonia pool was assumed. No correlation between glutamic acid content of the diet and specific radioactivity of CO 2 or atom-% 15 N excess of urinary N was observed. (author)

Glutamate may be an efferent transmitter that elicits inhibition in mouse taste buds.

Directory of Open Access Journals (Sweden)

Yijen A Huang

Full Text Available Recent studies suggest that l-glutamate may be an efferent transmitter released from axons innervating taste buds. In this report, we determined the types of ionotropic synaptic glutamate receptors present on taste cells and that underlie this postulated efferent transmission. We also studied what effect glutamate exerts on taste bud function. We isolated mouse taste buds and taste cells, conducted functional imaging using Fura 2, and used cellular biosensors to monitor taste-evoked transmitter release. The findings show that a large fraction of Presynaptic (Type III taste bud cells (∼50% respond to 100 µM glutamate, NMDA, or kainic acid (KA with an increase in intracellular Ca(2+. In contrast, Receptor (Type II taste cells rarely (4% responded to 100 µM glutamate. At this concentration and with these compounds, these agonists activate glutamatergic synaptic receptors, not glutamate taste (umami receptors. Moreover, applying glutamate, NMDA, or KA caused taste buds to secrete 5-HT, a Presynaptic taste cell transmitter, but not ATP, a Receptor cell transmitter. Indeed, glutamate-evoked 5-HT release inhibited taste-evoked ATP secretion. The findings are consistent with a role for glutamate in taste buds as an inhibitory efferent transmitter that acts via ionotropic synaptic glutamate receptors.

Glutamate may be an efferent transmitter that elicits inhibition in mouse taste buds.

Science.gov (United States)

Huang, Yijen A; Grant, Jeff; Roper, Stephen

2012-01-01

Recent studies suggest that l-glutamate may be an efferent transmitter released from axons innervating taste buds. In this report, we determined the types of ionotropic synaptic glutamate receptors present on taste cells and that underlie this postulated efferent transmission. We also studied what effect glutamate exerts on taste bud function. We isolated mouse taste buds and taste cells, conducted functional imaging using Fura 2, and used cellular biosensors to monitor taste-evoked transmitter release. The findings show that a large fraction of Presynaptic (Type III) taste bud cells (∼50%) respond to 100 µM glutamate, NMDA, or kainic acid (KA) with an increase in intracellular Ca(2+). In contrast, Receptor (Type II) taste cells rarely (4%) responded to 100 µM glutamate. At this concentration and with these compounds, these agonists activate glutamatergic synaptic receptors, not glutamate taste (umami) receptors. Moreover, applying glutamate, NMDA, or KA caused taste buds to secrete 5-HT, a Presynaptic taste cell transmitter, but not ATP, a Receptor cell transmitter. Indeed, glutamate-evoked 5-HT release inhibited taste-evoked ATP secretion. The findings are consistent with a role for glutamate in taste buds as an inhibitory efferent transmitter that acts via ionotropic synaptic glutamate receptors.

Glutamate requires NMDA receptors to modulate alpha2 adrenoceptor in medulla oblongata cultured cells of newborn rats.

Science.gov (United States)

Marinho da Silva, Sergio; Carrettiero, Daniel C; Chadi, Débora R F

2014-04-03

α2 Adrenoceptors (α2-ARs) are important in regulating the central control of blood pressure in medulla oblongata. However, it is unclear how this receptor is modulated by different receptors, especially the glutamatergic. In the present study, we studied the influence of ionotropic glutamatergic receptors over the α2-ARs in cultured cells of the medulla oblongata of newborn rats. For this purpose, the protein level of the α2-ARs was assessed after administration to the cultured cells of glutamate (glu), the agonists NMDA and kainate (KA), the NMDA receptor antagonist MK801 and the KA receptor antagonist DNQX. Results indicate that the α2-AR protein levels were increased after the treatments with glu and NMDA, and the addition of MK801 to this treatment thwarted this increase. Notwithstanding the fact that KA did not alter the receptor protein level, the combined treatment of DNQX with glu prevented the α2-AR protein modulation. In conclusion, the present study suggests that ionotropic glutamatergic receptors could be related to the α2-AR protein regulation in the medulla oblongata. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Influence of the glutamic acid content of the diet on the catabolic rate of labelled glutamic acid in rats. 2

International Nuclear Information System (INIS)

Wilke, A.; Simon, O.; Bergner, H.

1984-01-01

40 rats with a body weight of 100 g received 7 semisynthetic diets with different contents of glutamic acid and one diet contained whole-egg. A L-amino acid mixture corresponding to the pattern of egg protein was the protein source of the semisynthetic diets. Glutamic acid was supplemented succesively from 0 to 58 mol-% of the total amino acid content. On the 8th day of the experimental feeding the animals were labelled by subcutaneous injection of 14 C-glutamic acid. Subsequently the CO 2 and the 14 CO 2 excretion were measured for 24 hours. In this period 64 to 68 % of the injected radioactivity were recovered as 14 CO 2 . The curve pattern of 14 CO 2 excretion indicates two different processes of 14 CO 2 formation. One characterizing the direct degradation of glutamic acid to CO 2 with a high rate constant and a second one with a lower rate constant characterizing the 14 CO 2 formation via metabolites of glutamic acid. 77 % of the total 14 CO 2 excretion in 24 hours resulted from the direct oxidation of glutamic acid and 23 % from the oxidation of intermediates. When 14 CO 2 formation was measured 10 to 24 hours after injection of 14 C-glutamic acid a positive correlation to the content of glutamic acid in the diet was observed. The intestinal tissue contributes considerably to the catabolization of glutamic acid, however, there seems to exist an upper limit for this capacity. (author)

21 CFR 182.1047 - Glutamic acid hydrochloride.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride. (b...

A ketogenic diet modifies glutamate, gamma-aminobutyric acid and agmatine levels in the hippocampus of rats: A microdialysis study.

Science.gov (United States)

Calderón, Naima; Betancourt, Luis; Hernández, Luis; Rada, Pedro

2017-03-06

The ketogenic diet (KD) is acknowledged as an unconventional option in the treatment of epilepsy. Several lines of investigation point to a possible role of glutamate and gamma-aminobutyric acid (GABA) as main contributors in this protective effect. Other biomolecules could also be involved in the beneficial consequence of the KD, for example, the diamine agmatine has been suggested to block imidazole and glutamate NMDA receptor and serves as an endogenous anticonvulsant in different animal models of epilepsy. In the present report, we have used microdialysis coupled to capillary electrophoresis to monitor microdialysate levels of GABA, glutamate and agmatine in the hippocampus of rats submitted to a KD for 15days compared to rats on a normal rat chow diet. A significant increase in GABA and agmatine levels while no change in glutamate levels was observed. These results support the notion that the KD modifies different transmitters favoring inhibitory over excitatory neurotransmitters. Copyright © 2017 Elsevier B.V. All rights reserved.

Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models

Czech Academy of Sciences Publication Activity Database

Holubová, Kristína; Nekovářová, Tereza; Pistovčáková, J.; Šulcová, A.; Stuchlík, Aleš; Valeš, Karel

2014-01-01

Roč. 8, Apr 16 (2014), s. 130 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GAP303/12/1464; GA MZd(CZ) NT13403; GA TA ČR(CZ) TE01020028 Grant - others:GA MŠk(CZ) LM2011017; GA MŠk(CZ) ED1.1.00/02.0068 Program:ED Institutional support: RVO:67985823 Keywords : depression * anxiety * NMDA channel blocker * neuroactive steroid * 3a5b-pregnanolone glutamate Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

Radiometric microassay for glutamic acid decarboxylase

Energy Technology Data Exchange (ETDEWEB)

Maderdrut, J L [North Carolina Dept. of Mental Health, Raleigh (USA); North Carolina Univ., Chapel Hill (USA). School of Medicine)

1979-01-01

A simple method for purifying L-(/sup 3/H) glutamic acid and incubation conditions suitable for estimating L-glutamic acid decarboxylase activity are described. Routine and recycled cation-exchange procedure for separating ..gamma..-aminobutyric acid from L-glutamate are outlined and compared. Recycling increases the sensitivity of the cation-exchange method by 6-7 fold. L-Glutamate decarboxylase activity can be measured reliably in samples of embryonic neural tissue having wet-weights of approximately 1 ..mu..g. The cation-exchange method is compared with the anion-exchange and CO/sub 2/-trapping methods. L-Glutamate decarboxylase activity has been detected in the lumbar spinal cord of the chick embryo at Day 21/4 (stage 14) using the cation-exchange method. This is 5-6 days earlier than L-glutamate decarboxylase activity has been detected in embryonic neural tissue by previous investigators. L-Glutamate decarboxylase is present in the lumbar spinal cord at least as early as the birth of the first lumbar spinal cord neurons and at least 1-2 days before the initiation of synaptogenesis.

3 alpha 5 beta-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia

Czech Academy of Sciences Publication Activity Database

Valeš, Karel; Rambousek, Lukáš; Holubová, Kristína; Svoboda, Jan; Bubeníková-Valešová, V.; Chodounská, Hana; Vyklický ml., Ladislav; Stuchlík, Aleš

2012-01-01

Roč. 235, č. 1 (2012), s. 82-88 ISSN 0166-4328 R&D Projects: GA MZd(CZ) NS10365 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : schizophrenia-like behavior * MK-801 * use-dependent * NMDA antagonist * anxiety * pregnanolone glutamate * Carousel maze Subject RIV: FH - Neurology Impact factor: 3.327, year: 2012

Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

Science.gov (United States)

Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

2013-01-01

Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

Directory of Open Access Journals (Sweden)

Charles eDucrot

2013-10-01

Full Text Available Previous studies have shown that blockade of ventral midbrain (VM glutamate N-Methyl-D-Aspartate (NMDA receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VM neurons, a fast and short lasting depolarisation mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VM neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VM neuronal activity, we studied the effects of VM AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for two hours after bilateral VM microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(fquinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5ul/side and of a single dose (0.825 nmol/0.5ul/side of the NMDA antagonist, PPPA (2R,4S-4-(3-Phosphonopropyl-2-piperidinecarboxylic acid. NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VM sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected respectively into the anterior and posterior VM. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VM neurons, to modulate

Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents

International Nuclear Information System (INIS)

Luo, Jialie; Li, Wenming; Liu, Yuwei; Zhang, Wei; Fu, Hongjun; Lee, Nelson T.K.; Yu, Hua; Pang, Yuanping; Huang, Pingbo; Xia, Jun; Li, Zhi-Wang; Li, Chaoying; Han, Yifan

2007-01-01

Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC 50 value increased from 0.19 ± 0.03 μM to 0.41 ± 0.04 μM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia

Glutamate in schizophrenia: clinical and research implications.

Science.gov (United States)

Goff, D C; Wine, L

1997-10-30

The excitatory amino acids, glutamate and aspartate, are of interest to schizophrenia research because of their roles in neurodevelopment, neurotoxicity and neurotransmission. Recent evidence suggests that densities of glutamatergic receptors and the ratios of subunits composing these receptors may be altered in schizophrenia, although it is unclear whether these changes are primary or compensatory. Agents acting at the phencyclidine binding site of the NMDA receptor produce symptoms of schizophrenia in normal subjects, and precipitate relapse in patients with schizophrenia. The improvement of negative symptoms with agents acting at the glycine modulatory site of the NMDA receptor, as well as preliminary evidence that clozapine may differ from conventional neuroleptic agents in its effects on glutamatergic systems, suggest that clinical implications may follow from this model. While geriatric patients may be at increased risk for glutamate-mediated neurotoxicity, very little is known about the specific relevance of this model to geriatric patients with schizophrenia.

High-level exogenous glutamic acid-independent production of poly-(γ-glutamic acid) with organic acid addition in a new isolated Bacillus subtilis C10.

Science.gov (United States)

Zhang, Huili; Zhu, Jianzhong; Zhu, Xiangcheng; Cai, Jin; Zhang, Anyi; Hong, Yizhi; Huang, Jin; Huang, Lei; Xu, Zhinan

2012-07-01

A new exogenous glutamic acid-independent γ-PGA producing strain was isolated and characterized as Bacillus subtilis C10. The factors influencing the endogenous glutamic acid supply and the biosynthesis of γ-PGA in this strain were investigated. The results indicated that citric acid and oxalic acid showed the significant capability to support the overproduction of γ-PGA. This stimulated increase of γ-PGA biosynthesis by citric acid or oxalic acid was further proved in the 10 L fermentor. To understand the possible mechanism contributing to the improved γ-PGA production, the activities of four key intracellular enzymes were measured, and the possible carbon fluxes were proposed. The result indicated that the enhanced level of pyruvate dehydrogenase (PDH) activity caused by oxalic acid was important for glutamic acid synthesized de novo from glucose. Moreover, isocitrate dehydrogenase (ICDH) and glutamate dehydrogenase (GDH) were the positive regulators of glutamic acid biosynthesis, while 2-oxoglutarate dehydrogenase complex (ODHC) was the negative one. Copyright © 2012 Elsevier Ltd. All rights reserved.

Glutamate: Tastant and Neuromodulator in Taste Buds.

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Vandenbeuch, Aurelie; Kinnamon, Sue C

2016-07-01

In taste buds, glutamate plays a double role as a gustatory stimulus and neuromodulator. The detection of glutamate as a tastant involves several G protein-coupled receptors, including the heterodimer taste receptor type 1, member 1 and 3 as well as metabotropic glutamate receptors (mGluR1 and mGluR4). Both receptor types participate in the detection of glutamate as shown with knockout animals and selective antagonists. At the basal part of taste buds, ionotropic glutamate receptors [N-methyl-d-aspartate (NMDA) and non-NMDA] are expressed and participate in the modulation of the taste signal before its transmission to the brain. Evidence suggests that glutamate has an efferent function on taste cells and modulates the release of other neurotransmitters such as serotonin and ATP. This short article reviews the recent developments in the field with regard to glutamate receptors involved in both functions as well as the influence of glutamate on the taste signal. © 2016 American Society for Nutrition.

Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice.

Science.gov (United States)

Wolak, Małgorzata; Siwek, Agata; Szewczyk, Bernadeta; Poleszak, Ewa; Bystrowska, Beata; Moniczewski, Andrzej; Rutkowska, Anita; Młyniec, Katarzyna; Nowak, Gabriel

2015-06-01

The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals

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Krueger, Katharina; Gruner, Janina; Madeja, Michael; Musshoff, Ulrich [Universitaetsklinikum Muenster, Institut fuer Physiologie I, Muenster (Germany); Hartmann, Louise M.; Hirner, Alfred V. [Universitaet Duisburg-Essen, Institut fuer Umweltanalytik, Essen (Germany); Binding, Norbert [Universitaetsklinikum Muenster, Institut fuer Arbeitsmedizin, Muenster (Germany)

2006-08-15

Pentavalent and trivalent organoarsenic compounds belong to the major metabolites of inorganic arsenicals detected in humans. Recently, the question was raised whether the organic arsenicals represent metabolites of a detoxification process or methylated species with deleterious biological effects. In this study, the effects of trivalent arsenite (AsO{sub 3} {sup 3-}; iA{sup III}), the pentavalent organoarsenic compounds monomethylarsonic acid (CH{sub 3}AsO(OH){sub 2}; MMA{sup V}) and dimethylarsinic acid ((CH{sub 3}){sub 2}AsO(OH); DMA{sup V}) and the trivalent compounds monomethylarsonous acid (CH{sub 3}As(OH){sub 2}, MMA{sup III}) and dimethylarsinous acid ((CH{sub 3}){sub 2}As(OH); DMA{sup III}) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concentrations of 1-1,000 {mu}mol/l and the organic arsenical compounds were tested in concentrations of 0.1-100 {mu}mol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMA{sup V} and MMA{sup III} significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concentrations <10 {mu}mol/l, DMA{sup V} and DMA{sup III} significantly reduced NMDA-receptor mediated responses with threshold concentrations <0.1 {mu}mol/l; iA{sup III} had no effects on glutamate receptors of the NMDA type. MMA{sup III} and DMA{sup V} significantly reduced ion currents through {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concentrations <10 {mu}mol/l (MMA{sup III}) and <1 {mu}mol/l (DMA{sup V}). MMA{sup V} and iA{sup III} had no significant effects on glutamate receptors of the AMPA type. The effects of MMA{sup V}, MMA

Influence of the glutamic acid content of the diet on the catabolisc rate of labelled glutamic acid in rats. 1

International Nuclear Information System (INIS)

Bergner, H.; Wilke, A.; Simon, O.; Wolf, E.

1984-01-01

Male rats received in 8 groups of 10 animals each for a period of 7 days 7 synthetic diets and one semisynthetic diet on maintenance requirement level. A L-amino acid mixture corresponding to the pattern of egg protein without glutamic acid was the protein source of the synthetic diets. Glutamic acid was supplemented successively from 0 to 58 mol-% of the total amino acid content. The crude protein source of diet 8 was whole-egg powder. On the 8th day of experiment 5 animals per group were labelled by intragastric infusion with 14 C-glutamic acid. During the following 24 hours the excretion of CO 2 and 14 CO 2 was measured. Throughout the experimental feeding body weight was relative constant, however, when the synthetic diets were fed it was necessary to increase the daily amount of energy from 460 to 480 kJ/kg/sup 0.67/. The relative 14 CO 2 excretion within 24 hours was 68-75 % of the dose. However, the main part of the amount of radioactivity excreted during 24 hours was already found after 4 to 6 hours. Exponential functions calculated from the data of cumulative 14 CO 2 excretion suggest the existence of a fast process of 14 CO 2 formation directly from 14 C-glutamic acid, reaching a plateau within 2 hours and a slow process of oxidation of intermediates of glutamic acid metabolism, causing a continued 14 CO 2 formation even after 24 hours. The oxidation of 14 C-glutamic acid to CO 2 decreased 2 to 14 hours after labelling if the glutamic acid content of the diet increased. The same was found for the specific radioactivity of 14 CO 2 . A storage of intermediates of glutamic acid before degradation was assumed. (author)

Influence of Glutamic Acid on the Properties of Poly(xylitol glutamate sebacate Bioelastomer

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Weifu Dong

2013-11-01

Full Text Available In order to further improve the biocompatibility of xylitol based poly(xylitol sebacate (PXS bioelastomer, a novel kind of amino acid based poly(xylitol glutamate sebacate (PXGS has been successfully prepared in this work by melt polycondensation of xylitol, N-Boc glutamic acid and sebacic acid. Differential scanning calorimetry (DSC results indicated the glass-transition temperatures could be decreased by feeding N-Boc glutamic acid. In comparison to PXS, PXGS exhibited comparable tensile strength and much higher elongation at break at the same ratio of acid/xylitol. The introduction of glutamic acid increased the hydrophilicity and in vitro degradation rate of the bioelastomer. It was found that PXGS exhibited excellent properties, such as tensile properties, biodegradability and hydrophilicity, which could be easily tuned by altering the feeding monomer ratios. The amino groups in the PXGS polyester side chains are readily functionalized, thus the biomelastomers can be considered as potential biomaterials for biomedical application.

A radiometric microassay for glutamic acid decarboxylase

International Nuclear Information System (INIS)

Maderdrut, J.L.; North Carolina Univ., Chapel Hill

1979-01-01

A simple method for purifying L-[ 3 H] glutamic acid and incubation conditions suitable for estimating L-glutamic acid decarboxylase activity are described. Routine and recycled cation-exchange procedure for separating γ-aminobutyric acid from L-glutamate are outlined and compared. Recycling increases the sensitivity of the cation-exchange method by 6-7 fold. L-Glutamate decarboxylase activity can be measured reliably in samples of embryonic neural tissue having wet-weights of approximately 1 μg. The cation-exchange method is compared with the anion-exchange and CO 2 -trapping methods. L-Glutamate decarboxylase activity has been detected in the lumbar spinal cord of the chick embryo at Day 21/4 (stage 14) using the cation-exchange method. This is 5-6 days earlier than L-glutamate decarboxylase activity has been detected in embryonic neural tissue by previous investigators. L-Glutamate decarboxylase is present in the lumbar spinal cord at least as early as the birth of the first lumbar spinal cord neurons and at least 1-2 days before the initiation of synaptogenesis. (author)

Spermine modulation of the glutamateNMDA receptors is differentially responsive to conantokins in normal and alzheimer disease human cortex

International Nuclear Information System (INIS)

Ragnarsson, L.; Dodd, P.R.; Lewis, R.; University of Queensland, QLD

1998-01-01

Full text: The pharmacological characteristics of human N-methyl-D-aspartate (NMDA) receptors were examined in 12 control and 6 pathologically confirmed Alzheimer disease (AD) cases in six different brain areas, by studying their responses to MK-801, glutamate, spermine, and the NMDA receptor antagonists Ala(7)-conantokinG and Lys(7)-conantokinG. [ 3 H]MK801 binding assays performed by standard protocols on well-washed synoptic plasma membranes showed little variation in k D in all six brain areas, including comparisons between control and matched AD cases. b MAX values showed regional differences within control and AD cases, but there was no significant difference between groups in any of the brain regions. Maximal glutamate-enhanced [ 3 H]MK801 binding did not vary much between the brain regions or between control and AD cases, whereas maximal spermine-enhanced [ 3 H]MK-801 binding differed significantly between certain brain regions and between control and AD cases. In absolute terms in the control cases, the activation values were much lower in the spared regions, occipital and motor cortex, than in other areas; further, areas which are susceptible to damage showed reduced spermine activation in AD cases. These regional differences in the efficacy of spermine activation might be the result of local variations in the subunit composition of the NMDA receptor. Ala(7)-conantokinG and Lys(7)-conantokinG showed slight differences in potency, with the Ala(7) compound as the more potent. Both peptides produced 100% inhibition of spermine-enhanced [ 3 H]MK-801 binding in all brain areas, ana both gave lower IC 50 values in AD cases than in control cases. The significant differences in the inhibition of spermine-enhanced [ 3 H]MK-801 binding by the peptides between control and AD cases suggest that AD cases have a particular receptor subunit composition that is responsive to polyamines and which might make them more susceptible to excitotoxic damage. The spermine site

Influence of glutamic acid enantiomers on C-mineralization.

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Formánek, Pavel; Vranová, Valerie; Lojková, Lea

2015-02-01

Seasonal dynamics in the mineralization of glutamic acid enantiomers in soils from selected ecosystems was determined and subjected to a range of treatments: ambient x elevated CO2 level and meadow x dense x thinned forest environment. Mineralization of glutamic acid was determined by incubation of the soil with 2 mg L- or D-glutamic acid g(-1) of dry soil to induce the maximum respiration rate. Mineralization of glutamic acid enantiomers in soils fluctuates over the course of a vegetation season, following a similar trend across a range of ecosystems. Mineralization is affected by environmental changes and management practices, including elevated CO2 level and thinning intensity. L-glutamic acid metabolism is more dependent on soil type as compared to metabolism of its D-enantiomer. The results support the hypothesis that the slower rate of D- compared to L- amino acid mineralization is due to different roles in anabolism and catabolism of the soil microbial community. © 2014 Wiley Periodicals, Inc.

Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors

DEFF Research Database (Denmark)

Madsen, U; Brehm, L; Schaumburg, Kjeld

1990-01-01

The relationship between conformational flexibility and agonist or antagonist actions at the N-Methyl-D-aspartic acid (NMDA) subtype of central L-glutamic acid (GLU) receptors of a series of racemic piperidinedicarboxylic acids (PDAs) was studied. The conformational analyses were based on 1H NMR...... receptors. Each of the three cyclic acidic amino acids showing NMDA agonist activities was found to exist as an equilibrium mixture of two conformers in aqueous solution. In contrast, the NMDA antagonists cis-2,3-PDA and cis-2,4-PDA as well as the inactive compounds trans-2,5-PDA and cis-2,6-PDA were shown...

Glutamic acid and folic acid production in aerobic and anaerobic probiotics

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Zohre Taghi Abadi

2018-03-01

Full Text Available Introduction:From an industrial application or commercial point of view, glutamic acid is one of the most important amino acids and its microbial production has been reported from some bacteria. Regarding the role of probiotics to modulate human health and the ever-increasing demand of prebiotics in the food industry, in the current study, production of glutamic acid and folic acid from three probiotic bacteria (Bifidobacterium, Bifidobacterium bifidum, Sporolactobacillus was evaluated for the first time. Materials and methods: MRS broth and exclusive media was used for probiotic culture. The glutamic acid was identified using thin-layer chromatography and folic acid production was measured by folate kit. Each bacterium in terms of quality and quantity were measured by high pressure liquid chromatography. Results: Production of glutamic acid confirmed is based on the thin layer chromatography analysis and high pressure liquid chromatography results. In addition, it was observed that all three probiotics produce folic acid. The prevalence of folate in Bifidobacterium was measured as 315 mg/ml that was more than two other bacteria. Discussion and conclusion: To the best of our knowledge, this is the first report of microbial production of glutamic acid and folate from the probiotic bacteria. These beneficial bacteria can be used as a good source for mass production of these valuable compounds.

Excitatory amino acid receptors and disease.

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Meldrum, B S

1992-08-01

Recent advances in the molecular biology of excitatory amino acid receptors are reviewed. Evidence that drugs blocking the excitatory action of glutamate at the N-methyl-D-aspartate (NMDA) and non-NMDA receptors may be of clinical use in epilepsy, Parkinson's disease, cerebral ischaemia and trauma, acquired immune deficiency syndrome (AIDS) encephalopathy and neuropathic pain is summarized.

NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects.

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Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N

2018-05-16

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.

Parabrachial complex glutamate receptors modulate the cardiorespiratory response evoked from hypothalamic defense area.

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Díaz-Casares, A; López-González, M V; Peinado-Aragonés, C A; González-Barón, S; Dawid-Milner, M S

2012-08-16

To characterize the possible role of glutamate in the interaction between Hypothalamic Defense Area (HDA) and Parabrachial complex (PBc) nuclei, cardiorespiratory changes were analyzed in response to electrical stimulation of the HDA (1 ms pulses, 30-50 μA given at 100 Hz for 5s) before and after the microinjection of the nonspecific glutamate receptor antagonist kynurenic acid (50 nl, 5 nmol), NMDA receptor antagonist MK-801 (50 nl, 50 nmol), non-NMDA receptor antagonist CNQX (50 nl, 50 nmol) or metabotropic glutamate receptor antagonist MCPG (50 nl, 5 nmol) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (pHDA stimulation. Similarly, the magnitude of the tachycardia and the pressor response was decreased after the microinjection of MK-801 (pHDA stimulation but the respiratory response persisted unchanged after MK-801 or CNQX microinjection into the lPB. Kynurenic acid within the medial parabrachial region (mPB) abolished the tachycardia (pHDA stimulation. MK-801 and CNQX microinjection in this region decreased the magnitude of the tachycardia (pHDA stimulation was not changed after the microinjection of kynurenic acid, MK-801 or CNQX within the mPB. No changes were observed in the cardiorespiratory response evoked to HDA stimulation after MCPG microinjection within lPB and mPB. These results indicate that glutamate PBc receptors are involved in the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

Vesicular glutamate release from central axons contributes to myelin damage.

Science.gov (United States)

Doyle, Sean; Hansen, Daniel Bloch; Vella, Jasmine; Bond, Peter; Harper, Glenn; Zammit, Christian; Valentino, Mario; Fern, Robert

2018-03-12

The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.

Fast inhibition of glutamate-activated currents by caffeine.

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Nicholas P Vyleta

Full Text Available BACKGROUND: Caffeine stimulates calcium-induced calcium release (CICR in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release. METHODOLOGY/PRINCIPAL FINDINGS: Using the whole-cell patch-clamp technique we found that caffeine (20 mM reversibly increased the frequency and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs in neocortical neurons. The increase in mEPSC frequency is consistent with a presynaptic mechanism. Caffeine also reduced exogenously applied glutamate-activated currents, confirming a separate postsynaptic action. This inhibition developed in tens of milliseconds, consistent with block of channel currents. Caffeine (20 mM did not reduce currents activated by exogenous NMDA, indicating that caffeine block is specific to non-NMDA type glutamate receptors. CONCLUSIONS/SIGNIFICANCE: Caffeine-induced inhibition of mEPSC amplitude occurs through postsynaptic block of non-NMDA type ionotropic glutamate receptors. Caffeine thus has both pre and postsynaptic sites of action at excitatory synapses.

Mechanical stress activates NMDA receptors in the absence of agonists

OpenAIRE

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

2017-01-01

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor i...

Role of Ca+2 and other second messengers in excitatory amino acid receptor mediated neurodegeneration: clinical perspectives

DEFF Research Database (Denmark)

Schousboe, A; Belhage, B; Frandsen, A

1997-01-01

Neurodegeneration associated with neurological disorders such as epilepsy, Huntington's Chorea, Alzheimer's disease, and olivoponto cerebellar atrophy or with energy failure such as ischemia, hypoxia, and hypoglycemia proceeds subsequent to overexposure of neurons to excitatory amino acids of which...... glutamate and aspartate may be quantitatively the most important. The toxic action of glutamate and aspartate is mediated through activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) and non-NMDA subtypes. Antagonists for these receptors can act as neuroprotectants both in in vitro model...

[Determination of glutamic acid in biological material by capillary electrophoresis].

Science.gov (United States)

Narezhnaya, E; Krukier, I; Avrutskaya, V; Degtyareva, A; Igumnova, E A

2015-01-01

The conditions for the identification and determination of Glutamic acid by capillary zone electrophoresis without their preliminary derivatization have been optimized. The effect of concentration of buffer electrolyte and pH on determination of Glutamic acid has been investigated. It is shown that the 5 Mm borate buffer concentration and a pH 9.15 are optimal. Quantitative determination of glutamic acid has been carried out using a linear dependence between the concentration of the analyte and the area of the peak. The accuracy and reproducibility of the determination are confirmed by the method "introduced - found". Glutamic acid has been determined in the placenta homogenate. The duration of analysis doesn't exceed 30 minutes. The results showed a decrease in the level of glutamic acid in cases of pregnancy complicated by placental insufficiency compared with the physiological, and this fact allows to consider the level of glutamic acid as a possible marker of complicated pregnancy.

(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors

DEFF Research Database (Denmark)

Ahmadian, H; Nielsen, B; Bräuner-Osborne, Hans

1997-01-01

of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3......Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist...... microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM)....

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

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Bryan L Roth

Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

40 CFR 721.3821 - L-Glutamic acid, N-(1-oxododecyl)-.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false L-Glutamic acid, N-(1-oxododecyl... Substances § 721.3821 L-Glutamic acid, N-(1-oxododecyl)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as L-Glutamic acid, N-(1-oxododecyl)- (PMN P...

Complex formation between glutamic acid and molybdenum (VI)

International Nuclear Information System (INIS)

Gharib, Farrokh; Khorrami, S.A.; Sharifi, Sasan

1997-01-01

Equilibria of the reaction of molybdenum (VI) with L-glutamic acid have been studied in aqueous solution in the pH range 2.5 to 9.5, using spectrophotometric and optical rotation methods at constant ionic strength (0.15 mol dm -3 sodium perchlorate) and temperature 25 ± 0.1 degC. Our studies have shown that glutamic acid forms a mononuclear complex with Mo(VI) of the type MoO 3 L 2- at pH 5.5. The stability constant of this complexation and the dissociation constants of L-glutamic acid have been determined. (author). 17 refs., 2 figs., 4 tabs

Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

Science.gov (United States)

Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

2013-05-01

Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

Combination of aspartic acid and glutamic acid inhibits tumor cell proliferation.

Science.gov (United States)

Yamaguchi, Yoshie; Yamamoto, Katsunori; Sato, Yoshinori; Inoue, Shinjiro; Morinaga, Tetsuo; Hirano, Eiichi

2016-01-01

Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.

Novel Functional Properties of Drosophila CNS Glutamate Receptors

Energy Technology Data Exchange (ETDEWEB)

Li, Yan; Dharkar, Poorva; Han, Tae-Hee; Serpe, Mihaela; Lee, Chi-Hon; Mayer, Mark L.

2016-12-01

Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation.

Mutual diffusion coefficients of L-glutamic acid and monosodium L-glutamate in aqueous solutions at T = 298.15 K

International Nuclear Information System (INIS)

Ribeiro, Ana C.F.; Rodrigo, M.M.; Barros, Marisa C.F.; Verissimo, Luis M.P.; Romero, Carmen; Valente, Artur J.M.; Esteso, Miguel A.

2014-01-01

Highlights: • Interdiffusion coefficients of L-glutamic acid and sodium L-glutamate were measured. • The L-glutamic acid behaves as a monoprotic weak acid. • The sodium L-glutamate shows a symmetrical 1:1 non-associated behaviour. • Limiting diffusion coefficients and ionic conductivities were estimated. • Diffusion coefficients were discussed on the basis of the Onsager–Fuoss equations. - Abstract: Mutual diffusion coefficient values for binary aqueous solutions of both L-glutamic acid (H 2 Glu) and sodium L-glutamate (NaHGlu) were measured with the Taylor dispersion technique, at T = 298.15 K, and concentrations ranging from (0.001 to 0.100) mol · dm −3 . The results were discussed on the basis of the Onsager–Fuoss and the Nernst theoretical equations, by considering the H 2 Glu as a weak acid (monoprotic acid, with K 2 = 5.62 · 10 −5 ). The smaller values found for the acid with respect to those of the salt, confirm this association hypothesis. From the diffusion coefficient values at infinitesimal concentration, limiting ionic conductivities as well as the hydrodynamic radius of the hydrogen glutamate ion (HGlu − ) were derived and analyzed in terms of the chain methylene groups. The effect of different phenomena, such as association or complexation, were also taken into consideration and discussed. Values for the dissociation degree for H 2 Glu were also estimated

Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts Antidepressant-Like Properties in Animal Models.

Science.gov (United States)

Holubova, Kristina; Nekovarova, Tereza; Pistovcakova, Jana; Sulcova, Alexandra; Stuchlík, Ales; Vales, Karel

2014-01-01

A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. -3α5�

Neuromodulatory Effect of Thymoquinone in Attenuating Glutamate-Mediated Neurotoxicity Targeting the Amyloidogenic and Apoptotic Pathways

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Ibram Amin Fouad

2018-04-01

Full Text Available Overexposure of the glutamatergic N-methyl-d-aspartate (NMDA receptor to the excitatory neurotransmitter l-glutamic acid leads to neuronal cell death by excitotoxicity as a result of increased intracellular Ca2+, mitochondrial dysfunction, and apoptosis. Moreover, it was previously reported that prolonged activation of the NMDA receptor increased beta-amyloid (Aβ levels in the brain. Thymoquinone (TQ, the active constituent of Nigella sativa seeds, has been shown to have potent antioxidant and antiapoptotic effects. The aim of the present study was to explore the neuromodulatory effects of different doses of TQ (2.5 and 10 mg/kg against apoptotic cell death and Aβ formation resulting from glutamate administration in rats using vitamin E as a positive control. Behavioral changes were assessed using Y-maze and Morris water maze tests for evaluating spatial memory and cognitive functions. Caspase-3, Lactate dehydrogenase, Aβ-42, and cytochrome c gene expression were determined. TQ-treated groups showed significant decreases in the levels of all tested biochemical and behavioral parameters compared with the glutamate-treated group. These findings demonstrated that TQ has a promising neuroprotective activity against glutamate-induced neurotoxicity and this effect is mediated through its anti-amyloidogenic, antioxidant, and antiapoptotic activities.

Synthesis and distribution of L-glutamic acid with three different labels

International Nuclear Information System (INIS)

Cohen, M.B.; Spolter, Leonard; Chia Chin Chang; MacDonald, N.S.

1982-01-01

A study was performed to compare the distribution of C-11 L-glutamic acid, labeled on the carboxyl group of either the alpha or gamma carbon with that of N-13 L-glutamic acid in order to determine if the position of the label is of importance in the study of the distribution of glutamic acid

Glutamic Acid Selective Chemical Cleavage of Peptide Bonds.

Science.gov (United States)

Nalbone, Joseph M; Lahankar, Neelam; Buissereth, Lyssa; Raj, Monika

2016-03-04

Site-specific hydrolysis of peptide bonds at glutamic acid under neutral aqueous conditions is reported. The method relies on the activation of the backbone amide chain at glutamic acid by the formation of a pyroglutamyl (pGlu) imide moiety. This activation increases the susceptibility of a peptide bond toward hydrolysis. The method is highly specific and demonstrates broad substrate scope including cleavage of various bioactive peptides with unnatural amino acid residues, which are unsuitable substrates for enzymatic hydrolysis.

Excretion and intestinal absorption of tritiated glutamic acid by carp, Cyprinus Carpio

International Nuclear Information System (INIS)

Watabe, Terushia; Kistner, G.

1986-01-01

Excretion and intestinal absorption of tritiated glutamic acid by carp was investigated. Approximately 80% of orally administered tritium was excreted at a half life value of 1.4 h and an observed slower excretion of 7 days for the remainder. Tritium incorporated in glutamic acid was efficiently retained at the site of absorption, i.e. intestine, liver, gill, kidney, blood and muscle. A dual marking experiment using tritiated glutamic acid and 14 C-market glutamic acid showed higher excretion of tritium by factors 2.0 to 4.9 than that of 14 C. Tritiated glutamic acid is considered to be mainly incorporated in the citric acid cycle soon after administration and the release of tritium in tritiated water through the cycle is assumed as causing the initial rapid excretion of tritium in carp. The intestinal absorption of glutamic acid was likely to depend on its concentration in the administered solution. The maximum level of absorption is estimated to be 0.1 m mol/0.5 h for one year old carp. The results obtained here would make it possible to estimate the tritium contamination of fish due to tritiated glutamic acid entering the food chain. (orig.)

Poly-gamma-glutamic acid a substitute of salivary protein statherin

International Nuclear Information System (INIS)

Qamar, Z.; Rahim, Z.B.H.A.; Fatima, T.

2016-01-01

The modus operandi of salivary proteins in reducing the kinetics of enamel dissolution during simulated caries challenges is thought to be associated with interaction of glutamic acid residues with human teeth surfaces. Japanese traditional food stuff natto is rich with chain of repeating glutamic acid residues linked by gamma-peptide bond and hence, named poly-gamma-glutamic acid (PGGA). It is a naturally occurring polypeptide and may therefore perform similar caries inhibitory functions as statherin. (author)

Mechanical stress activates NMDA receptors in the absence of agonists.

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Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

2017-01-03

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

Increased response to glutamate in small diameter dorsal root ganglion neurons after sciatic nerve injury.

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Kerui Gong

Full Text Available Glutamate in the peripheral nervous system is involved in neuropathic pain, yet we know little how nerve injury alters responses to this neurotransmitter in primary sensory neurons. We recorded neuronal responses from the ex-vivo preparations of the dorsal root ganglia (DRG one week following a chronic constriction injury (CCI of the sciatic nerve in adult rats. We found that small diameter DRG neurons (30 µm were unaffected. Puff application of either glutamate, or the selective ionotropic glutamate receptor agonists alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA and kainic acid (KA, or the group I metabotropic receptor (mGluR agonist (S-3,5-dihydroxyphenylglycine (DHPG, induced larger inward currents in CCI DRGs compared to those from uninjured rats. N-methyl-D-aspartate (NMDA-induced currents were unchanged. In addition to larger inward currents following CCI, a greater number of neurons responded to glutamate, AMPA, NMDA, and DHPG, but not to KA. Western blot analysis of the DRGs revealed that CCI resulted in a 35% increase in GluA1 and a 60% decrease in GluA2, the AMPA receptor subunits, compared to uninjured controls. mGluR1 receptor expression increased by 60% in the membrane fraction, whereas mGluR5 receptor subunit expression remained unchanged after CCI. These results show that following nerve injury, small diameter DRG neurons, many of which are nociceptive, have increased excitability and an increased response to glutamate that is associated with changes in receptor expression at the neuronal membrane. Our findings provide further evidence that glutamatergic transmission in the periphery plays a role in nociception.

Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats.

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Stern, Javier E; Potapenko, Evgeniy S

2013-08-15

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.

Glutamine and glutamate: Nonessential or essential amino acids?

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Malcolm Watford

2015-09-01

Full Text Available Glutamine and glutamate are not considered essential amino acids but they play important roles in maintaining growth and health in both neonates and adults. Although glutamine and glutamate are highly abundant in most feedstuffs there is increasing evidence that they may be limiting during pregnancy, lactation and neonatal growth, particularly when relatively low protein diets are fed. Supplementation of diets with glutamine, glutamate or both at 0.5 to 1.0% to both suckling and recently weaned piglets improves intestinal and immune function and results in better growth. In addition such supplementation to the sow prevents some of the loss of lean body mass during lactation, and increases milk glutamine content. However, a number of important questions related to physiological condition, species under study and the form and amount of the supplements need to be addressed before the full benefits of glutamine and glutamate supplementation in domestic animal production can be realized. Keywords: Amino acid, Glutamate, Glutamine, Lactation, Pregnancy, Growth

Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

Science.gov (United States)

Moreau, J. L.; Pieri, L.; Prud'hon, B.

1989-01-01

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats.

Science.gov (United States)

Bespalov, A Y; Medvedev, I O; Sukhotina, I A; Zvartau, E E

2001-04-01

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

Characterisation of the human NMDA receptor subunit NR3A glycine binding site

DEFF Research Database (Denmark)

Nilsson, A; Duan, J; Mo-Boquist, L-L

2007-01-01

In this study, we characterise the binding site of the human N-methyl-d-aspartate (NMDA) receptor subunit NR3A. Saturation radioligand binding of the NMDA receptor agonists [(3)H]-glycine and [(3)H]-glutamate showed that only glycine binds to human NR3A (hNR3A) with high affinity (K(d)=535nM (277...

Biobased synthesis of acrylonitrile from glutamic acid

NARCIS (Netherlands)

Notre, le J.E.L.; Scott, E.L.; Franssen, M.C.R.; Sanders, J.P.M.

2011-01-01

Glutamic acid was transformed into acrylonitrile in a two step procedure involving an oxidative decarboxylation in water to 3-cyanopropanoic acid followed by a decarbonylation-elimination reaction using a palladium catalyst

Therapeutic effects of glutamic acid in piglets challenged with deoxynivalenol.

Science.gov (United States)

Wu, Miaomiao; Xiao, Hao; Ren, Wenkai; Yin, Jie; Tan, Bie; Liu, Gang; Li, Lili; Nyachoti, Charles Martin; Xiong, Xia; Wu, Guoyao

2014-01-01

The mycotoxin deoxynivalenol (DON), one of the most common food contaminants, primarily targets the gastrointestinal tract to affect animal and human health. This study was conducted to examine the protective function of glutamic acid on intestinal injury and oxidative stress caused by DON in piglets. Twenty-eight piglets were assigned randomly into 4 dietary treatments (7 pigs/treatment): 1) uncontaminated control diet (NC), 2) NC+DON at 4 mg/kg (DON), 3) NC+2% glutamic acid (GLU), and 4) NC+2% glutamic acid + DON at 4 mg/kg (DG). At day 15, 30 and 37, blood samples were collected to determine serum concentrations of CAT (catalase), T-AOC (total antioxidant capacity), H2O2 (hydrogen peroxide), NO (nitric oxide), MDA (maleic dialdehyde), DAO (diamine oxidase) and D-lactate. Intestinal morphology, and the activation of Akt/mTOR/4EBP1 signal pathway, as well as the concentrations of H2O2, MDA, and DAO in kidney, liver and small intestine, were analyzed at day 37. Results showed that DON significantly (Pglutamic acid supplementation according to the change of oxidative parameters in blood and tissues. Meanwhile, DON caused obvious intestinal injury from microscopic observations and permeability indicators, which was alleviated by glutamic acid supplementation. Moreover, the inhibition of DON on Akt/mTOR/4EBP1 signal pathway was reduced by glutamic acid supplementation. Collectively, these data suggest that glutamic acid may be a useful nutritional regulator for DON-induced damage manifested as oxidative stress, intestinal injury and signaling inhibition.

NMDA receptor function during senescence: implication on cognitive performance

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Ashok eKumar

2015-12-01

Full Text Available N-methyl-D-aspartate (NMDA receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.

Pharmacological characterization of NMDA-like receptors in the single-celled organism Paramecium primaurelia.

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Ramoino, Paola; Candiani, Simona; Pittaluga, Anna Maria; Usai, Cesare; Gallus, Lorenzo; Ferrando, Sara; Milanese, Marco; Faimali, Marco; Bonanno, Giambattista

2014-02-01

Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single-celled organism Paramecium and thus

Genetic and metabolic engineering for microbial production of poly-γ-glutamic acid.

Science.gov (United States)

Cao, Mingfeng; Feng, Jun; Sirisansaneeyakul, Sarote; Song, Cunjiang; Chisti, Yusuf

2018-05-28

Poly-γ-glutamic acid (γ-PGA) is a natural biopolymer of glutamic acid. The repeating units of γ-PGA may be derived exclusively from d-glutamic acid, or l-glutamic acid, or both. The monomer units are linked by amide bonds between the α-amino group and the γ-carboxylic acid group. γ-PGA is biodegradable, edible and water-soluble. It has numerous existing and emerging applications in processing of foods, medicines and cosmetics. This review focuses on microbial production of γ-PGA via genetically and metabolically engineered recombinant bacteria. Strategies for improving production of γ-PGA include modification of its biosynthesis pathway, enhancing the production of its precursor (glutamic acid), and preventing loss of the precursor to competing byproducts. These and other strategies are discussed. Heterologous synthesis of γ-PGA in industrial bacterial hosts that do not naturally produce γ-PGA is discussed. Emerging trends and the challenges affecting the production of γ-PGA are reviewed. Copyright © 2018. Published by Elsevier Inc.

21 CFR 573.500 - Condensed, extracted glutamic acid fermentation product.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Condensed, extracted glutamic acid fermentation product. 573.500 Section 573.500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... fermentation product. Condensed, extracted glutamic acid fermentation product may be safely used in animal feed...

A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain

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Yang Qi

2009-12-01

Full Text Available Abstract The midbrain periaqueductal grey (PAG is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp, one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.

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Zhao Han

Full Text Available Excessive activation of the N-methyl-D-aspartic acid (NMDA type glutamate receptors (NMDARs causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl-2-imidazoline (2-BFI, an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9 M(-1 sec(-1 and off rate (Koff = 0.67±0.02 sec(-1 than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.

Chronic intermittent hypoxia impairs heart rate responses to AMPA and NMDA and induces loss of glutamate receptor neurons in nucleus ambiguous of F344 rats.

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Yan, Binbin; Li, Lihua; Harden, Scott W; Gozal, David; Lin, Ying; Wead, William B; Wurster, Robert D; Cheng, Zixi Jack

2009-02-01

Chronic intermittent hypoxia (CIH), as occurs in sleep apnea, impairs baroreflex-mediated reductions in heart rate (HR) and enhances HR responses to electrical stimulation of vagal efferent. We tested the hypotheses that HR responses to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the nucleus ambiguous (NA) are reduced in CIH-exposed rats and that this impairment is associated with degeneration of glutamate receptor (GluR)-immunoreactive NA neurons. Fischer 344 rats (3-4 mo) were exposed to room air (RA) or CIH for 35-50 days (n = 18/group). At the end of the exposures, AMPA (4 pmol, 20 nl) and NMDA (80 pmol, 20 nl) were microinjected into the same location of the left NA (-200 microm to +200 microm relative to caudal end of area postrema; n = 6/group), and HR and arterial blood pressure responses were measured. In addition, brain stem sections at the level of -800, -400, 0, +400, and +800 microm relative to obex were processed for AMPA and NMDA receptor immunohistochemistry. The number of NA neurons expressing AMPA receptors and NMDA receptors (NMDARs) was quantified. Compared with RA, we found that after CIH 1) HR responses to microinjection of AMPA into the left NA were reduced (RA -290 +/- 30 vs. CIH -227 +/- 15 beats/min, P neurons expressing GluRs contributes to impaired baroreflex control of HR in rats exposed to CIH.

40 CFR 721.3820 - L-Glutamic acid, N-(1-oxododecyl)-, disodium salt.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false L-Glutamic acid, N-(1-oxododecyl... Specific Chemical Substances § 721.3820 L-Glutamic acid, N-(1-oxododecyl)-, disodium salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as L-Glutamic...

Glutamic Acid as Enhancer of Protein Synthesis Kinetics in Hepatocytes from Old Rats.

Science.gov (United States)

Brodsky, V Y; Malchenko, L A; Butorina, N N; Lazarev Konchenko, D S; Zvezdina, N D; Dubovaya, T K

2017-08-01

Dense cultures of hepatocytes from old rats (~2 years old, body weight 530-610 g) are different from similar cultures of hepatocytes from young rats by the low amplitude of protein synthesis rhythm. Addition of glutamic acid (0.2, 0.4, or 0.6 mg/ml) into the culture medium with hepatocytes of old rats resulted in increase in the oscillation amplitudes of the protein synthesis rhythm to the level of young rats. A similar action of glutamic acid on the protein synthesis kinetics was observed in vivo after feeding old rats with glutamic acid. Inhibition of metabotropic receptors of glutamic acid with α-methyl-4-carboxyphenylglycine (0.01 mg/ml) abolished the effect of glutamic acid. The amplitude of oscillation of the protein synthesis rhythm in a cell population characterizes synchronization of individual oscillations caused by direct cell-cell communications. Hence, glutamic acid, acting as a receptor-dependent transmitter, enhanced direct cell-cell communications of hepatocytes that were decreased with aging. As differentiated from other known membrane signaling factors (gangliosides, norepinephrine, serotonin, dopamine), glutamic acid can penetrate into the brain and thus influence the communications and protein synthesis kinetics that are disturbed with aging not only in hepatocytes, but also in neurons.

Inhibitory mechanism of l-glutamic acid on spawning of the starfish Patiria (Asterina) pectinifera.

Science.gov (United States)

Mita, Masatoshi

2017-03-01

l-Glutamic acid was previously identified as an inhibitor of spawning in the starfish Patiria (Asterina) pectinifera; this study examined how l-glutamic acid works. Oocyte release from ovaries of P. pectinifera occurred after germinal vesicle breakdown (GVBD) and follicular envelope breakdown (FEBD) when gonads were incubated ex vivo with either relaxin-like gonad-stimulating peptide (RGP) or 1-methyladenine (1-MeAde). l-Glutamic acid blocked this spawning phenotype, causing the mature oocytes to remain within the ovaries. Neither RGP-induced 1-MeAde production in ovarian follicle cells nor 1-MeAde-induced GVBD and FEBD was affected by l-glutamic acid. l-Glutamic acid may act through metabotropic receptors in the ovaries to inhibit spawning, as l-(+)-2-amino-4-phosphonobutyric acid, an agonist for metabotropic glutamate receptors, also inhibited spawning induced by 1-MeAde. Application of acetylcholine (ACH) to ovaries under inhibitory conditions with l-glutamic acid, however, brought about spawning, possibly by inducing contraction of the ovarian wall to discharge mature oocytes from the ovaries concurrently with GVBD and FEBD. Thus, l-glutamic acid may inhibit ACH secretion from gonadal nerve cells in the ovary. Mol. Reprod. Dev. 84: 246-256, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Binding of L-glutamic acid to non-receptor materials

International Nuclear Information System (INIS)

Periyasamy, S.; Ito, M.; Chiu, T.H.

1986-01-01

[ 3 H]L-glutamic acid ([ 3 H]Glu) binding to microfuge tubes, glass fiber filters, and glass tubes was studied in 4 buffers (50 mM, pH 7.4 at 4 0 C). Binding assays were done at 0-4 0 C. Binding to these materials was negligible in the absence of external force, but was increased by suction or centrifugation in Tris-HCl or Tris-citrate buffer. The force-induced binding was much less or was eliminated in Tris-acetate or HEPES-KOH buffer. [ 3 H]Glu binding to microfuge tubes was inhibited by L- but not D- isomers of glutamate and aspartate. DL-2-amino-7-phosphonoheptanoic acid was without effect. Other compounds that showed low to moderate inhibitory activity were N-methyl-D-aspartate, quisqualate, L-glutamic acid diethyl ester. N-methyl-L-aspartate, kainate, and 2-amino-4-phosphonobutyrate. Binding was inhibited by denatured P 2 membrane preparation in Tris-acetate buffer was used. It is suggested that Tris-acetate or HEPES-KOH buffer should be used in the glutamate binding assay

Intramolecular synergistic effect of glutamic acid, cysteine and glycine against copper corrosion in hydrochloric acid solution

International Nuclear Information System (INIS)

Zhang Daquan; Xie Bin; Gao Lixin; Cai Qirui; Joo, Hyung Goun; Lee, Kang Yong

2011-01-01

The corrosion protection of copper by glutamic acid, cysteine, glycine and their derivative (glutathione) in 0.5 M hydrochloric acid solution has been studied by the electrochemical impedance spectroscopy and cyclic voltammetry. The inhibition efficiency of the organic inhibitors on copper corrosion increases in the order: glutathione > cysteine > cysteine + glutamic acid + glycine > glutamic acid > glycine. Maximum inhibition efficiency for cysteine reaches about 92.9% at 15 mM concentration level. The glutathione can give 96.4% inhibition efficiency at a concentration of 10 mM. The molecular structure parameters were obtained by PM3 (Parametric Method 3) semi-empirical calculation. The intramolecular synergistic effect of glutamic acid, cysteine and glycine moieties in glutathione is attributed to the lower energy of the lowest unoccupied molecular orbital (E LUMO ) level and to the excess hetero-atom adsorption centers and the bigger coverage on the copper surface.

Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.

Science.gov (United States)

Betzen, Christian; White, Robin; Zehendner, Christoph M; Pietrowski, Eweline; Bender, Bianca; Luhmann, Heiko J; Kuhlmann, Christoph R W

2009-10-15

N-methyl-d-aspartate receptor (NMDA-R)-mediated oxidative stress has been implicated in blood-brain barrier (BBB) disruption in a variety of neuropathological diseases. Although some interactions between both phenomena have been elucidated, possible influences of reactive oxygen species (ROS) on the NMDA-R itself have so far been neglected. The objective of this study was to examine how the cerebroendothelial NMDA-R is affected by exposure to oxidative stress and to assess possible influences on BBB integrity. RT-PCR confirmed several NMDA-R subunits (NR1, NR2B-D) expressed in the bEnd3 cell line (murine cerebrovascular endothelial cells). NR1 protein expression after exposure to ROS was observed via in-cell Western. The functionality of the expressed NMDA-R was determined by measuring DiBAC fluorescence in ROS-preexposed cells upon stimulation with the specific agonist NMDA. Finally, the effects on barrier integrity were evaluated using the ECIS system to detect changes in monolayer impedance upon NMDA-R stimulation after exposure to ROS. The expression of NR1 significantly (p<0.001) increased 72 h after 30 min exposure to superoxide (+33.8+/-7.5%), peroxynitrite (+84.9+/-10.7%), or hydrogen peroxide (+92.8+/-7.6%), resulting in increased cellular response to NMDA-R stimulation and diminished monolayer impedance. We conclude that oxidative stress upregulates NMDA-R on cerebrovascular endothelium and thus heightens susceptibility to glutamate-induced BBB disruption.

De-coupling of blood flow and metabolism in the rat brain induced by glutamate

International Nuclear Information System (INIS)

Hirose, Shinichiro; Momosaki, Sotaro; Sasaki, Kazunari; Hosoi, Rie; Abe, Kohji; Inoue, Osamu; Gee, A.

2009-01-01

Glutamate plays an essential role in neuronal cell death in many neurological disorders. In this study, we examined both glucose metabolism and cerebral blood flow in the same rat following infusion of glutamate or ibotenic acid using the dual-tracer technique. The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptor antagonist, on the changes in the glucose metabolism and cerebral blood flow induced by glutamate were also examined. The rats were microinjected with glutamate (1 μmol/μl, 2 μl) or ibotenic acid (10 μg/μl, 1 μl) into the right striatum, and dual-tracer autoradiograms of [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]iofetamine (IMP) were obtained. MK-801 and NBQX were injected intravenously about 45 and 30 min, respectively, after the infusion of glutamate. De-coupling of blood flow and metabolism was noted in the glutamate-infused hemisphere (as assessed by no alteration of [ 18 F]FDG uptake and significant decrease of [ 14 C]IMP uptake). Pretreatments with MK-801, NBQX, or combined use of MK-801 and NBQX did not affect the de-coupling of the blood flow and metabolism induced by glutamate. A histochemical study revealed that about 20% neuronal cell death had occurred in the striatum at 105 min after the infusion of glutamate. In addition, a significant increase of the [ 18 F]FDG uptake and decrease of [ 14 C]IMP uptake were also seen in the rat brain infused with ibotenic acid. These results indicate that glutamate and ibotenic acid caused a significant de-coupling of blood flow and glucose metabolism in the intact rat brain during the early phase of neurodegeneration. It is necessary to evaluate the relation between metabotropic glutamate receptors and de-coupling of blood flow and metabolism. (author)

ATP secretion from nerve trunks and Schwann cells mediated by glutamate.

Science.gov (United States)

Liu, Guo Jun; Bennett, Max R

2003-11-14

ATP release from rat sciatic nerves and from cultured Schwann cells isolated from the nerves was investigated using an online bioluminescence technique. ATP was released in relatively large amounts from rat sciatic nerve trunks during electrical stimulation. This release was blocked by the sodium channel inhibitor tetrodotoxin and the non-NMDA glutamate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Schwann cells isolated from the nerve trunks did not release ATP when electrically stimulated but did in response to glutamate in a concentration-dependent manner. Glutamate-stimulated ATP release was inhibited by specific non-competitive AMPA receptor antagonist GYKI 52466 and competitive non-NMDA receptor antagonist CNQX. Glutamate-stimulated ATP release was decreased by inhibition of anion transporter inhibitors by furosemide, cystic fibrosis transmembrane conductance regulator by glibenclamide and exocytosis by botulinum toxin A, indicating that anion transporters and exocytosis provide the main secretion mechanisms for ATP release from the Schwann cells.

Development of a novel ultrasensitive enzyme immunoassay for human glutamic acid decarboxylase 65 antibody.

Science.gov (United States)

Numata, Satoshi; Katakami, Hideki; Inoue, Shinobu; Sawada, Hirotake; Hashida, Seiichi

2016-07-01

We developed a novel, ultrasensitive enzyme immunoassay (immune complex transfer enzyme immunoassay) for determination of glutamic acid decarboxylase autoantibody concentrations in serum samples from patients with type 2 diabetes. We developed an immune complex transfer enzyme immunoassay for glutamic acid decarboxylase autoantibody and measured glutamic acid decarboxylase autoantibody from 22 patients with type 1 diabetes, 29 patients with type 2 diabetes, and 32 healthy controls. A conventional ELISA kit identified 10 patients with type 1 diabetes and one patient with type 2 diabetes as glutamic acid decarboxylase autoantibody positive, whereas 15 patients with type 1 diabetes and six patients with type 2 diabetes were identified as glutamic acid decarboxylase autoantibody positive using immune complex transfer enzyme immunoassay. Immune complex transfer enzyme immunoassay is a highly sensitive and specific assay for glutamic acid decarboxylase autoantibody and might be clinically useful for diabetic onset prediction and early diagnosis. © The Author(s) 2016.

Glutamic Acid – the Main Dietary Amino Acid – and Blood Pressure: The INTERMAP Study

Science.gov (United States)

Stamler, Jeremiah; Brown, Ian J; Daviglus, Martha L; Chan, Queenie; Kesteloot, Hugo; Ueshima, Hirotsugu; Zhao, Liancheng; Elliott, Paul

2009-01-01

Background Data are available indicating an independent inverse relationship of dietary vegetable protein to the blood pressure (BP) of individuals. Here we assess whether BP is associated with glutamic acid intake (the predominant dietary amino acid, especially in vegetable protein) and with each of four other amino acids higher relatively in vegetable than animal protein (proline, phenylalanine, serine, cystine). Methods and Results Cross-sectional epidemiological study; 4,680 persons ages 40–59 -- 17 random population samples in China, Japan, U.K., U.S.A.; BP measurement 8 times at 4 visits; dietary data (83 nutrients, 18 amino acids) from 4 standardized multi-pass 24-hour dietary recalls and 2 timed 24-hour urine collections. Dietary glutamic acid (percent of total protein intake) was inversely related to BP. Across multivariate regression models (Model 1 controlled for age, gender, sample, through Model 5 controlled for 16 non-nutrient and nutrient possible confounders) estimated average BP differences associated with glutamic acid intake higher by 4.72% total dietary protein (2 s.d.) were −1.5 to −3.0 mm Hg systolic and −1.0 to −1.6 mm Hg diastolic (Z-values −2.15 to −5.11). Results were similar for the glutamic acid-BP relationship with each other amino acid also in the model, e.g., with control for 15 variables plus proline, systolic/diastolic pressure differences −2.7/−2.0 (Z −2.51, −2.82). In these 2-amino acid models, higher intake (2 s.d.) of each other amino acid was associated with small BP differences and Z-values. Conclusions Dietary glutamic acid may have independent BP lowering effects, possibly contributing to the inverse relation of vegetable protein to BP. PMID:19581495

Independent and additive effects of glutamic acid and methionine on yeast longevity.

Science.gov (United States)

Wu, Ziyun; Song, Lixia; Liu, Shao Quan; Huang, Dejian

2013-01-01

It is established that glucose restriction extends yeast chronological and replicative lifespan, but little is known about the influence of amino acids on yeast lifespan, although some amino acids were reported to delay aging in rodents. Here we show that amino acid composition greatly alters yeast chronological lifespan. We found that non-essential amino acids (to yeast) methionine and glutamic acid had the most significant impact on yeast chronological lifespan extension, restriction of methionine and/or increase of glutamic acid led to longevity that was not the result of low acetic acid production and acidification in aging media. Remarkably, low methionine, high glutamic acid and glucose restriction additively and independently extended yeast lifespan, which could not be further extended by buffering the medium (pH 6.0). Our preliminary findings using yeasts with gene deletion demonstrate that glutamic acid addition, methionine and glucose restriction prompt yeast longevity through distinct mechanisms. This study may help to fill a gap in yeast model for the fast developing view that nutrient balance is a critical factor to extend lifespan.

Bioconversion of sugar cane molasses into glutamic acid by gamma irradiated corynebacterium glutamicum

International Nuclear Information System (INIS)

El-Batal, A.I.

1996-01-01

Corynebacterium glutamicum (ATCC 13058) was used for glutamic acid production from sugar cane molasses which contain sufficient. The addition of 5 units ml 4 of penicillin G was superior in glutamic acid production (11.5 g L 4 ). Tweens and their saturated fatty acids were effective on the accumulation of glutamic acid in the culture medium and the maximum yield (16.6 g L 4 ) was the addition of 5 mg ml 4 Tween 40. Gamma irradiation prior to Tween-40 treatment of bacterial cells resulted in an obvious increase in glutamic acid production and it was maximum (23.72 g L 4 ) at 0.1 k Gy exposure dose of inocula. 5 tabs

Microscopic picture of the aqueous solvation of glutamic acid

NARCIS (Netherlands)

Leenders, E.J.M.; Bolhuis, P.G.; Meijer, E.J.

2008-01-01

We present molecular dynamics simulations of glutamic acid and glutamate solvated in water, using both density functional theory (DFT) and the Gromos96 force field. We focus on the microscopic aspects of the solvation−particularly on the hydrogen bond structures and dynamics−and investigate the

Effects of phosphoenolpyruvate carboxylase desensitization on glutamic acid production in Corynebacterium glutamicum ATCC 13032.

Science.gov (United States)

Wada, Masaru; Sawada, Kazunori; Ogura, Kotaro; Shimono, Yuta; Hagiwara, Takuya; Sugimoto, Masakazu; Onuki, Akiko; Yokota, Atsushi

2016-02-01

Phosphoenolpyruvate carboxylase (PEPC) in Corynebacterium glutamicum ATCC13032, a glutamic-acid producing actinobacterium, is subject to feedback inhibition by metabolic intermediates such as aspartic acid and 2-oxoglutaric acid, which implies the importance of PEPC in replenishing oxaloacetic acid into the TCA cycle. Here, we investigated the effects of feedback-insensitive PEPC on glutamic acid production. A single amino-acid substitution in PEPC, D299N, was found to relieve the feedback control by aspartic acid, but not by 2-oxoglutaric acid. A simple mutant, strain R1, having the D299N substitution in PEPC was constructed from ATCC 13032 using the double-crossover chromosome replacement technique. Strain R1 produced glutamic acid at a concentration of 31.0 g/L from 100 g/L glucose in a jar fermentor culture under biotin-limited conditions, which was significantly higher than that of the parent, 26.0 g/L (1.19-fold), indicative of the positive effect of desensitized PEPC on glutamic acid production. Another mutant, strain DR1, having both desensitized PEPC and PYK-gene deleted mutations, was constructed in a similar manner using strain D1 with a PYK-gene deleted mutation as the parent. This mutation had been shown to enhance glutamic acid production in our previous study. Although marginal, strain D1 produced higher glutamic acid, 28.8 g/L, than ATCC13032 (1.11-fold). In contrast, glutamic acid production by strain DR-1 was elevated up to 36.9 g/L, which was 1.42-fold higher than ATCC13032 and significantly higher than the other three strains. The results showed a synergistic effect of these two mutations on glutamic acid production in C. glutamicum. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Glutamic acid decarboxylase isoform distribution in transgenic mouse septum: an anti-GFP immunofluorescence study.

Science.gov (United States)

Verimli, Ural; Sehirli, Umit S

2016-09-01

The septum is a basal forebrain region located between the lateral ventricles in rodents. It consists of lateral and medial divisions. Medial septal projections regulate hippocampal theta rhythm whereas lateral septal projections are involved in processes such as affective functions, memory formation, and behavioral responses. Gamma-aminobutyric acidergic neurons of the septal region possess the 65 and 67 isoforms of the enzyme glutamic acid decarboxylase. Although data on the glutamic acid decarboxylase isoform distribution in the septal region generally appears to indicate glutamic acid decarboxylase 67 dominance, different studies have given inconsistent results in this regard. The aim of this study was therefore to obtain information on the distributions of both of these glutamic acid decarboxylase isoforms in the septal region in transgenic mice. Two animal groups of glutamic acid decarboxylase-green fluorescent protein knock-in transgenic mice were utilized in the experiment. Brain sections from the region were taken for anti-green fluorescent protein immunohistochemistry in order to obtain estimated quantitative data on the number of gamma-aminobutyric acidergic neurons. Following the immunohistochemical procedures, the mean numbers of labeled cells in the lateral and medial septal nuclei were obtained for the two isoform groups. Statistical analysis yielded significant results which indicated that the 65 isoform of glutamic acid decarboxylase predominates in both lateral and medial septal nuclei (unpaired two-tailed t-test p glutamic acid decarboxylase isoform 65 in the septal region in glutamic acid decarboxylase-green fluorescent protein transgenic mice.

Relationship between Glutamate Dysfunction and Symptoms and Cognitive Function in Psychosis

OpenAIRE

Merritt, Kate; McGuire, Philip; Egerton, Alice

2013-01-01

The glutamate hypothesis of schizophrenia, proposed over two decades ago, originated following the observation that administration of drugs that block NMDA glutamate receptors, such as ketamine, could induce schizophrenia-like symptoms. Since then, this hypothesis has been extended to describe how glutamate abnormalities may disturb brain function and underpin psychotic symptoms and cognitive impairments. The glutamatergic system is now a major focus for the development of new compounds in sc...

40 CFR 180.1187 - L-glutamic acid; exemption from the requirement of a tolerance.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false L-glutamic acid; exemption from the... Exemptions From Tolerances § 180.1187 L-glutamic acid; exemption from the requirement of a tolerance. L-glutamic acid is exempt from the requirement of a tolerance on all food commodities when used in accordance...

NMDA Receptors in Glial Cells: Pending Questions.

Science.gov (United States)

Dzamba, David; Honsa, Pavel; Anderova, Miroslava

2013-05-01

Glutamate receptors of the N-methyl-D-aspartate (NMDA) type are involved in many cognitive processes, including behavior, learning and synaptic plasticity. For a long time NMDA receptors were thought to be the privileged domain of neurons; however, discoveries of the last 25 years have demonstrated their active role in glial cells as well. Despite the large number of studies in the field, there are many unresolved questions connected with NMDA receptors in glia that are still a matter of debate. The main objective of this review is to shed light on these controversies by summarizing results from all relevant works concerning astrocytes, oligodendrocytes and polydendrocytes (also known as NG2 glial cells) in experimental animals, further extended by studies performed on human glia. The results are divided according to the study approach to enable a better comparison of how findings obtained at the mRNA level correspond with protein expression or functionality. Furthermore, special attention is focused on the NMDA receptor subunits present in the particular glial cell types, which give them special characteristics different from those of neurons - for example, the absence of Mg(2+) block and decreased Ca(2+) permeability. Since glial cells are implicated in important physiological and pathophysiological roles in the central nervous system (CNS), the last part of this review provides an overview of glial NMDA receptors with respect to ischemic brain injury.

A novel stereospecific synthesis of 14C labeled 1-glutamic acid

International Nuclear Information System (INIS)

Wurz, R.E.; Kepner, R.E.; Webb, A.D.

1989-01-01

A stereospecific synthesis of 4- 14 C-1-glutamic acid was completed in five steps from sodium 2- 14 C-acetate. The morpholine derived enamine of ethyl pyruvate was reacted with ethyl 2- 14 C-bromoacetate to give after hydrolysis diethyl 4- 14 C-2-oxoglutarate. The 2-oxoglutarate was reacted with hydroxylamine hydrochloride to give diethyl 4-14C-2-hydroxyiminoglutarate which was then reduced with a LiAlH4, (-)-N-methylephedrine and 3,5-dimethylphenol mixture to give 4- 14 C-1-glutamic acid. The 4- 14 C-1-glutamic acid was used in investigations into the biosynthesis of gamma-lactones in sherries

Effects of aromatic amino acids on glutamate-induced neuronal cell death

International Nuclear Information System (INIS)

Zafar, Z.; Sumners, C.

2005-01-01

Glutamate accumulation is believed to lead to overstimulation of glutamate receptors which results in neuronal death. The protective effects of aromatic amino acids on glutamate induced neuronal cell death were examined using rat cerebral cortical neurons. Neuronal death is quantified by measuring lactate dehydrogenase (LDH) using a spectrophotometric microtiter plate reader (ELISA reader). Neuronal cells were incubated with varying doses of glutamate plus or minus the aromatic amino acid D-Phenylalanine (D-Phe) for different time periods to observe protection against cytotoxicity. Percent cytotoxicity was seen to follow a dose dependent rise with increasing concentrations of glutamate, reaching a plateau at around 100 -500 uM glutamate. Lower levels of cytotoxicity were achieved with cell exposed to D-Phe and Dibromo tyrosine (DBrT). 48-hour experimental runs were also carried out to further investigate the mode of action of D-Phe. It was found that the difference between cytotoxicity levels of control cells and protected cells was higher over longer time. (author)

Secretory phospholipase A2-mediated neuronal cell death involves glutamate ionotropic receptors

DEFF Research Database (Denmark)

Kolko, Miriam; de Turco, Elena B; Diemer, Nils Henrik

2002-01-01

To define the significance of glutamate ionotropic receptors in sPLA -mediated neuronal cell death we used the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist PNQX. In primary neuronal cell cultures both MK-801 and PNQX inhibited sPLA - and glutamate-induced neuronal death. [ H...

Glutamic Acid - Amino Acid, Neurotransmitter, and Drug - Is Responsible for Protein Synthesis Rhythm in Hepatocyte Populations in vitro and in vivo.

Science.gov (United States)

Brodsky, V Y; Malchenko, L A; Konchenko, D S; Zvezdina, N D; Dubovaya, T K

2016-08-01

Primary cultures of rat hepatocytes were studied in serum-free media. Ultradian protein synthesis rhythm was used as a marker of cell synchronization in the population. Addition of glutamic acid (0.2 mg/ml) to the medium of nonsynchronous sparse cultures resulted in detection of a common protein synthesis rhythm, hence in synchronization of the cells. The antagonist of glutamic acid metabotropic receptors MCPG (0.01 mg/ml) added together with glutamic acid abolished the synchronization effect; in sparse cultures, no rhythm was detected. Feeding rats with glutamic acid (30 mg with food) resulted in protein synthesis rhythm in sparse cultures obtained from the rats. After feeding without glutamic acid, linear kinetics of protein synthesis was revealed. Thus, glutamic acid, a component of blood as a non-neural transmitter, can synchronize the activity of hepatocytes and can form common rhythm of protein synthesis in vitro and in vivo. This effect is realized via receptors. Mechanisms of cell-cell communication are discussed on analyzing effects of non-neural functions of neurotransmitters. Glutamic acid is used clinically in humans. Hence, a previously unknown function of this drug is revealed.

Type II and III Taste Bud Cells Preferentially Expressed Kainate Glutamate Receptors in Rats.

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Lee, Sang-Bok; Lee, Cil-Han; Kim, Se-Nyun; Chung, Ki-Myung; Cho, Young-Kyung; Kim, Kyung-Nyun

2009-12-01

Glutamate-induced cobalt uptake reveals that non-NMDA glutamate receptors (GluRs) are present in rat taste bud cells. Previous studies involving glutamate induced cobalt staining suggest this uptake mainly occurs via kainate type GluRs. It is not known which of the 4 types of taste bud cells express subunits of kainate GluR. Circumvallate and foliate papillae of Sprague-Dawley rats (45~60 days old) were used to search for the mRNAs of subunits of non-NMDA GluRs using RT-PCR with specific primers for GluR1-7, KA1 and KA2. We also performed RT-PCR for GluR5, KA1, PLCbeta2, and NCAM/SNAP 25 in isolated single cells from taste buds. Taste epithelium, including circumvallate or foliate papilla, express mRNAs of GluR5 and KA1. However, non-taste tongue epithelium expresses no subunits of non-NMDA GluRs. Isolated single cell RT-PCR reveals that the mRNAs of GluR5 and KA1 are preferentially expressed in Type II and Type III cells over Type I cells.

Purification and characterization of gamma poly glutamic acid from newly Bacillus licheniformis NRC20.

Science.gov (United States)

Tork, Sanaa E; Aly, Magda M; Alakilli, Saleha Y; Al-Seeni, Madeha N

2015-03-01

γ-poly glutamic acid (γ-PGA) has received considerable attention for pharmaceutical and biomedical applications. γ-PGA from the newly isolate Bacillus licheniformis NRC20 was purified and characterized using diffusion distance agar plate, mass spectrometry and thin layer chromatography. All analysis indicated that γ-PGA is a homopolymer composed of glutamic acid. Its molecular weight was determined to be 1266 kDa. It was composed of L- and D-glutamic acid residues. An amplicon of 3050 represents the γ-PGA-coding genes was obtained, sequenced and submitted in genbank database. Its amino acid sequence showed high similarity with that obtained from B. licheniformis strains. The bacterium NRC 20 was independent of L-glutamic acid but the polymer production enhanced when cultivated in medium containing L-glutamic acid as the sole nitrogen source. Finally we can conclude that γ-PGA production from B. licheniformis NRC20 has many promised applications in medicine, industry and nanotechnology. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of glutamic acid analogues on identifiable giant neurones, sensitive to beta-hydroxy-L-glutamic acid, of an African giant snail (Achatina fulica Férussac).

Science.gov (United States)

Nakajima, T.; Nomoto, K.; Ohfune, Y.; Shiratori, Y.; Takemoto, T.; Takeuchi, H.; Watanabe, K.

1985-01-01

The effects of the seven glutamic acid analogues, alpha-kainic acid, alpha-allo-kainic acid, domoic acid, erythro-L-tricholomic acid, DL-ibotenic acid, L-quisqualic acid and allo-gamma-hydroxy-L-glutamic acid were examined on six identifiable giant neurones of an African giant snail (Achatina fulica Férussac). The neurones studied were: PON (periodically oscillating neurone), d-RPLN (dorsal-right parietal large neurone), VIN (visceral intermittently firing neurone), RAPN (right anterior pallial neurone), FAN (frequently autoactive neurone) and v-RCDN (ventral-right cerebral distinct neurone). Of these, d-RPLN and RAPN were excited by the two isomers (erythro- and threo-) of beta-hydroxy-L-glutamic acid (L-BHGA), whereas PON, VIN, FAN and v-RCDN were inhibited. L-Glutamic acid (L-Glu) had virtually no effect on these neurones. alpha-Kainic acid and domoic acid showed marked excitatory effects, similar to those of L-BHGA, on d-RPLN and RAPN. Their effective potency quotients (EPQs), relative to the more effective isomer of L-BHGA were: 0.3 for both substances on d-RPLN, and 1 for alpha-kainic acid and 3-1 for domoic acid on RAPN. alpha-Kainic acid also had excitatory effects on FAN and v-RCDN (EPQ for both: 0.3), which were inhibited by L-BHGA but excited by gamma-aminobutyric acid (GABA). Erythro-L-tricholomic acid showed marked effects, similar to those of L-BHGA, on VIN (EPQ: 0.3) and RAPN (EPQ: 3-1), but produced weaker effects on PON and d-RPLN (EPQ: 0.1). DL-Ibotenic acid produced marked effects, similar to those of L-BHGA, on PON, VIN (EPQ for both: 1) and RAPN (EPQ: 1-0.3), but had weak effects on d-RPLN (EPQ: less than 0.1) and FAN (EPQ: 0.1). It had excitatory effects on v-RCDN (EPQ: 0.1). This neurone was inhibited by L-BHGA but excited by GABA. L-Quisqualic acid showed the same effects as L-BHGA on all of the neurones examined (EPQ range 30-0.1). It was the most potent of the compounds tested on RAPN (EPQ: 30-10), FAN (EPQ: 30) and v-RCDN (EPQ: 3). alpha

Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models.

Directory of Open Access Journals (Sweden)

Karel eVales

2014-04-01

Full Text Available A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive NMDA receptor antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDA receptor (NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze PG displayed anxiolytic-like properties. In forced swimming PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders.

Baseline dietary glutamic acid intake and the risk of colorectal cancer: The Rotterdam study.

Science.gov (United States)

Viana Veloso, Gilson G; Franco, Oscar H; Ruiter, Rikje; de Keyser, Catherina E; Hofman, Albert; Stricker, Bruno C; Kiefte-de Jong, Jessica C

2016-03-15

Animal studies have shown that glutamine supplementation may decrease colon carcinogenesis, but any relation with glutamine or its precursors has not been studied in humans. The primary aim of this study was to assess whether dietary glutamic acid intake was associated with colorectal cancer (CRC) risk in community-dwelling adults. A secondary aim was to evaluate whether the association could be modified by the body mass index (BMI). This study was embedded in the Rotterdam study, which included a prospective cohort from 1990 onward that consisted of 5362 subjects who were 55 years old or older and were free of CRC at the baseline. Glutamic acid was calculated as a percentage of the total protein intake with a validated food frequency questionnaire at the baseline. Incident cases of CRC were pathology-based. During follow-up, 242 subjects developed CRC. Baseline dietary glutamic acid intake was significantly associated with a lower risk of developing CRC (hazard ratio [HR] per percent increase in glutamic acid of protein, 0.78; 95% confidence interval [CI], 0.62-0.99). After stratification for BMI, the risk reduction for CRC by dietary glutamic acid was 42% for participants with a BMI ≤ 25 kg/m(2) (HR per percent increase in glutamic acid of protein, 0.58; 95% CI, 0.40-0.85), whereas no association was found in participants with a BMI > 25 kg/m(2) (HR per percent increase in glutamic acid of protein, 0.97; 95% CI, 0.73-1.31). Our data suggest that baseline dietary glutamic acid intake is associated with a lower risk of developing CRC, but this association may be mainly present in nonoverweight subjects. © 2015 American Cancer Society.

[A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954].

Science.gov (United States)

Häßler, Frank; Weirich, Steffen

2017-09-01

A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954 Glutamic acid was commonly used in the treatment of intellectually disabled children in the 50s. Koch reported first results of an observation of 140 children treated with glutamic acid in 1952. In this line is the multi-arm placebo-controlled study reported here. The original study protocols were available. 58 children with speech problems who attending a school of special needs received glutamic acid, or vitamin B, or St.-John's-wort. The effect of glutamic acid was in few cases an improvement of attention. On the other hand restlessness and stutter increased. The majority of all reported a weight loss. The treatment with vitamin B showed a positive effect concerning concentration. The treatment with St.-John's wort was stopped caused by headache and vomiting in eight of nine cases. The results of the study reported here are unpublished. The reason may be that until the 60s the effects of glutamic acid in the treatment of intellectually disabled children were in generally overestimated.

Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells.

Science.gov (United States)

Ferrari, Luiz Fernando; Lotufo, Celina Monteiro; Araldi, Dionéia; Rodrigues, Marcos A; Macedo, Larissa P; Ferreira, Sérgio H; Parada, Carlos Amilcar

2014-12-23

The present study evaluated the role of N-methyl-D-aspartate receptors (NMDARs) expressed in the dorsal root ganglia (DRG) in the inflammatory sensitization of peripheral nociceptor terminals to mechanical stimulation. Injection of NMDA into the fifth lumbar (L5)-DRG induced hyperalgesia in the rat hind paw with a profile similar to that of intraplantar injection of prostaglandin E2 (PGE2), which was significantly attenuated by injection of the NMDAR antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) in the L5-DRG. Moreover, blockade of DRG AMPA receptors by the antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect in the PGE2-induced hyperalgesia in the paw, showing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG plays an important role in the peripheral inflammatory hyperalgesia. In following experiments we observed attenuation of PGE2-induced hyperalgesia in the paw by the knockdown of NMDAR subunits NR1, NR2B, NR2D, and NR3A with antisense-oligodeoxynucleotide treatment in the DRG. Also, in vitro experiments showed that the NMDA-induced sensitization of cultured DRG neurons depends on satellite cell activation and on those same NMDAR subunits, suggesting their importance for the PGE2-induced hyperalgesia. In addition, fluorescent calcium imaging experiments in cultures of DRG cells showed induction of calcium transients by glutamate or NMDA only in satellite cells, but not in neurons. Together, the present results suggest that the mechanical inflammatory nociceptor sensitization is dependent on glutamate release at the DRG and subsequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG.

[3H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors

International Nuclear Information System (INIS)

Benke, D.; Honer, M.; Mohler, H.; Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C.

1999-01-01

Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [ 3 H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [ 3 H]CGP 61594 labeled with high affinity (K D =23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [ 3 H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [ 3 H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [ 3 H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Conformation of poly(γ-glutamic acid) in aqueous solution.

Science.gov (United States)

Muroga, Yoshio; Nakaya, Asami; Inoue, Atsuki; Itoh, Daiki; Abiru, Masaya; Wada, Kaori; Takada, Masako; Ikake, Hiroki; Shimizu, Shigeru

2016-04-01

Local conformation and overall conformation of poly(γ-DL-glutamic acid) (PγDLGA) and poly(γ-L-glutamic acid) (PγLGA) in aqueous solution was studied as a function of degree of ionization ε by (1) H-NMR, circular dichroism, and potentiometric titration. It was clarified that their local conformation is represented by random coil over an entire ε range and their overall conformation is represented by expanded random-coil in a range of ε > ε(*) , where ε(*) is about 0.3, 0.35, 0.45, and 0.5 for added-salt concentration of 0.02M, 0.05M, 0.1M, and 0.2M, respectively. In a range of ε acidic media. © 2015 Wiley Periodicals, Inc.

Searsia species with affinity to the N-methyl-d-aspartic acid (NMDA) receptor

DEFF Research Database (Denmark)

Jäger, Anna; Knap, D.M.; Nielsen, Birgitte

2012-01-01

Species of Searsia are used in traditional medicine to treat epilepsy. Previous studies on S. dentata and S. pyroides have shown that this is likely mediated via the N-methyl-d-aspartic acid (NMDA) receptor. Ethanolic extracts of leaves of six Searsia species were tested in a binding assay...

Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site

DEFF Research Database (Denmark)

Kvist, Trine; Steffensen, Thomas Bielefeldt; Greenwood, Jeremy R

2013-01-01

NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glyci...... screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design....

NMDA receptors and memory encoding.

Science.gov (United States)

Morris, Richard G M

2013-11-01

It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can

Compromised NMDA/Glutamate Receptor Expression in Dopaminergic Neurons Impairs Instrumental Learning, But Not Pavlovian Goal Tracking or Sign Tracking

Science.gov (United States)

James, Alex S; Pennington, Zachary T; Tran, Phu; Jentsch, James David

2015-01-01

Two theories regarding the role for dopamine neurons in learning include the concepts that their activity serves as a (1) mechanism that confers incentive salience onto rewards and associated cues and/or (2) contingency teaching signal reflecting reward prediction error. While both theories are provocative, the causal role for dopamine cell activity in either mechanism remains controversial. In this study mice that either fully or partially lacked NMDARs in dopamine neurons exclusively, as well as appropriate controls, were evaluated for reward-related learning; this experimental design allowed for a test of the premise that NMDA/glutamate receptor (NMDAR)-mediated mechanisms in dopamine neurons, including NMDA-dependent regulation of phasic discharge activity of these cells, modulate either the instrumental learning processes or the likelihood of pavlovian cues to become highly motivating incentive stimuli that directly attract behavior. Loss of NMDARs in dopamine neurons did not significantly affect baseline dopamine utilization in the striatum, novelty evoked locomotor behavior, or consumption of a freely available, palatable food solution. On the other hand, animals lacking NMDARs in dopamine cells exhibited a selective reduction in reinforced lever responses that emerged over the course of instrumental learning. Loss of receptor expression did not, however, influence the likelihood of an animal acquiring a pavlovian conditional response associated with attribution of incentive salience to reward-paired cues (sign tracking). These data support the view that reductions in NMDAR signaling in dopamine neurons affect instrumental reward-related learning but do not lend support to hypotheses that suggest that the behavioral significance of this signaling includes incentive salience attribution.

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

Science.gov (United States)

Jentsch, J D; Roth, R H

1999-03-01

Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

Evidence that glutamate mediates axon-to-Schwann cell signaling in the squid.

Science.gov (United States)

Lieberman, E M; Abbott, N J; Hassan, S

1989-01-01

High-frequency stimulation (100 Hz) of isolated giant axons of the small squid Alloteuthis subulata and the large squid Loligo forbesi caused the periaxonal Schwann cell resting potential (Em = -40 mV) to hyperpolarize up to 11 mV in direct proportion to train duration and action potential amplitude. In both species, the Schwann cell also hyperpolarized up to 17 mV with the application of L-glutamate (10(-9) to 10(-6) M), in a dose-dependent manner. By contrast, in the presence of 10(-8) M d-tubocurarine (d-TC) to block the cholinergic component of the Schwann cell response, Schwann cells depolarized 8-9 mV during electrical stimulation of the axon or application of L-glutamate. In the presence of 10(-5) M 2-amino-4-phosphonobutyrate (2-APB), the hyperpolarization to glutamate and to axon stimulation was blocked, whereas the cholinergic (carbachol-induced) hyperpolarization was unaffected. In experiments with Alloteuthis, L-aspartate (10(-7) M) also caused a Schwann cell hyperpolarization, but this was not blocked by 2-APB. In tests with glutamate receptor agonists and antagonists, quisqualate (10(-5) M) produced a hyperpolarization blocked by 10(-4) M L-glutamic acid diethylester (GDEE), which also blocked the response to axonal stimulation. Kainic acid (10(-4) M) also caused a hyperpolarization, but n-methyl-D-aspartate (NMDA; 10(-4) M), ibotenate (10(-5) M), alpha-amino-3-hydroxy-5-methyl-isoxazole proprionate (AMPA; (10(-4) M), and isethionate (10(-5) M) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis of Biobased Succinonitrile from Glutamic Acid and Glutamine

NARCIS (Netherlands)

Lammens, T.M.; Nôtre, Le J.; Franssen, M.C.R.; Scott, E.L.; Sanders, J.P.M.

2011-01-01

Succinonitrile is the precursor of 1,4-diaminobutane, which is used for the industrial production of polyamides. This paper describes the synthesis of biobased succinonitrile from glutamic acid and glutamine, amino acids that are abundantly present in many plant proteins. Synthesis of the

Techno-economic assessment of the production of bio-based chemicals from glutamic acid

NARCIS (Netherlands)

Lammens, T.M.; Gangarapu, S.; Franssen, M.C.R.; Scott, E.L.; Sanders, J.P.M.

2012-01-01

In this review, possible process steps for the production of bio-based industrial chemicals from glutamic acid are described, including a techno-economic assessment of all processes. The products under investigation were those that were shown to be synthesized from glutamic acid on lab-scale, namely

[{sup 3}H]CGP 61594, the first photoaffinity ligand for the glycine site of NMDA receptors

Energy Technology Data Exchange (ETDEWEB)

Benke, D.; Honer, M.; Mohler, H. [Institute of Pharmacology, ETH and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich (Switzerland); Heckendorn, R.; Pozza, M.F.; Allgeier, H.; Angst, C. [NS Research, Novartis Pharma AG, CH-4002 Basle (Switzerland)

1999-02-01

Activation of NMDA receptors requires the presence of glycine as a coagonist which binds to a site that is allosterically linked to the glutamate binding site. To identify the protein constituents of the glycine binding site in situ the photoaffinity label [{sup 3}H]CGP 61594 was synthesized. In reversible binding assays using crude rat brain membranes, [{sup 3}H]CGP 61594 labeled with high affinity (K{sub D}=23 nM) the glycine site of the NMDA receptor. This was evident from the Scatchard analysis, the displacing potencies of various glycine site ligands and the allosteric modulation of [{sup 3}H]CGP 61594 binding by ligands of the glutamate and polyamine sites. Electrophysiological experiments in a neocortical slice preparation identified CGP 61594 as a glycine antagonist. Upon UV-irradiation, a protein band of 115 kDa was specifically photolabeled by [{sup 3}H]CGP 61594 in brain membrane preparations. The photolabeled protein was identified as the NR1 subunit of the NMDA receptor by NR1 subunit-specific immunoaffinity chromatography. Thus, [{sup 3}H]CGP 61594 is the first photoaffinity label for the glycine site of NMDA receptors. It will serve as a tool for the identification of structural elements that are involved in the formation of the glycine binding domain of NMDA receptors in situ and will thereby complement the mutational analysis of recombinant receptors. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Contribution of glutamate decarboxylase in Lactobacillus reuteri to acid resistance and persistence in sourdough fermentation.

Science.gov (United States)

Su, Marcia S; Schlicht, Sabine; Gänzle, Michael G

2011-08-30

Acid stress impacts the persistence of lactobacilli in industrial sourdough fermentations, and in intestinal ecosystems. However, the contribution of glutamate to acid resistance in lactobacilli has not been demonstrated experimentally, and evidence for the contribution of acid resistance to the competitiveness of lactobacilli in sourdough is lacking. It was therefore the aim of this study to investigate the ecological role of glutamate decarboxylase in L. reuteri. A gene coding for a putative glutamate decarboxylase, gadB, was identified in the genome of L. reuteri 100-23. Different from the organization of genetic loci coding for glutamate decarboxylase in other lactic acid bacteria, gadB was located adjacent to a putative glutaminase gene, gls3. An isogenic deletion mutant, L. reuteri ∆gadB, was generated by a double crossover method. L. reuteri 100-23 but not L. reuteri ∆gadB converted glutamate to γ-aminobutyrate (GABA) in phosphate butter (pH 2.5). In sourdough, both strains converted glutamine to glutamate but only L. reuteri 100-23 accumulated GABA. Glutamate addition to phosphate buffer, pH 2.5, improved survival of L. reuteri 100-23 100-fold. However, survival of L. reuteri ∆gadB remained essentially unchanged. The disruption of gadB did not affect growth of L. reuteri in mMRS or in sourdough. However, the wild type strain L. reuteri 100-23 displaced L. reuteri ∆gadB after 5 cycles of fermentation in back-slopped sourdough fermentations. The conversion of glutamate to GABA by L. reuteri 100-23 contributes to acid resistance and to competitiveness in industrial sourdough fermentations. The organization of the gene cluster for glutamate conversion, and the availability of amino acids in cereals imply that glutamine rather than glutamate functions as the substrate for GABA formation. The exceptional coupling of glutamine deamidation to glutamate decarboxylation in L. reuteri likely reflects adaptation to cereal substrates.

Properties of glutamate-gated ion channels in horizontal cells of the perch retina.

Science.gov (United States)

Schmidt, K F

1997-08-01

The effect of two different concentrations of L-glutamate and kainate on the gating kinetics of amino acid-sensitive non-NMDA channels were studied in cultured teleost retinal horizontal cells by single-channel recording and by noise analysis of whole-cell currents. When the glutamate agonist kainate was applied clearly parabolic mean-variance relations of whole-cell membrane currents (up to 3000 pA) indicated that this agonist was acting on one type of channels with a conductance of 5-10 pS. The cells were less sensitive when L-glutamate was used as the agonist and in most cases whole-cell currents amounted to less than 200 pA. The mean-variance relation of glutamate induced currents was complex, indicating that more than one type of channel opening could be involved. Power spectra of whole-cell currents were fitted with two Lorentzians with time constants of approx. 1 and 5-20 msec. Effects on amplitudes and time constants of agonist concentrations are demonstrated. Two categories of unitary events with mean open times of approx. 1 and 7 msec and conductances of approx. 7 and 12 pS, respectively, were obtained in single-channel recordings from cell-attached patches at different concentrations of glutamate in the pipette.

Evaluation of glutamic acid and glycine as sources of nonessential amino acids for lake trout (Salvelinus namaycush) and rainbow trout (Salmo gairdnerii)

Science.gov (United States)

Hughes, S.G.

1985-01-01

1. A semi-purified test diet which contained either glutamic acid or glycine as the major source of nonessential amino acids (NEAA) was fed to lake and rainbow trout.2. Trout fed the diet containing glutamic acid consistently showed better growth and feed conversion efficiencies than those fed the diets containing glycine.3. The data indicate that these trout utilize glutamic acid more efficiently than glycine when no other major sources of NEAA are present.

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Energy Technology Data Exchange (ETDEWEB)

Lind, Genevieve E.; Mou, Tung-Chung; Tamborini, Lucia; Pomper, Martin G.; De Micheli, Carlo; Conti, Paola; Pinto, Andrea; Hansen, Kasper B. (JHU); (Milan); (Montana)

2017-07-31

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

Conformational analysis of glutamic acid: a density functional approach using implicit continuum solvent model.

Science.gov (United States)

Turan, Başak; Selçuki, Cenk

2014-09-01

Amino acids are constituents of proteins and enzymes which take part almost in all metabolic reactions. Glutamic acid, with an ability to form a negatively charged side chain, plays a major role in intra and intermolecular interactions of proteins, peptides, and enzymes. An exhaustive conformational analysis has been performed for all eight possible forms at B3LYP/cc-pVTZ level. All possible neutral, zwitterionic, protonated, and deprotonated forms of glutamic acid structures have been investigated in solution by using polarizable continuum model mimicking water as the solvent. Nine families based on the dihedral angles have been classified for eight glutamic acid forms. The electrostatic effects included in the solvent model usually stabilize the charged forms more. However, the stability of the zwitterionic form has been underestimated due to the lack of hydrogen bonding between the solute and solvent; therefore, it is observed that compact neutral glutamic acid structures are more stable in solution than they are in vacuum. Our calculations have shown that among all eight possible forms, some are not stable in solution and are immediately converted to other more stable forms. Comparison of isoelectronic glutamic acid forms indicated that one of the structures among possible zwitterionic and anionic forms may dominate over the other possible forms. Additional investigations using explicit solvent models are necessary to determine the stability of charged forms of glutamic acid in solution as our results clearly indicate that hydrogen bonding and its type have a major role in the structure and energy of conformers.

Mutations of the Corynebacterium glutamicum NCgl1221 Gene, Encoding a Mechanosensitive Channel Homolog, Induce l-Glutamic Acid Production▿

OpenAIRE

Nakamura, Jun; Hirano, Seiko; Ito, Hisao; Wachi, Masaaki

2007-01-01

Corynebacterium glutamicum is a biotin auxotroph that secretes l-glutamic acid in response to biotin limitation; this process is employed in industrial l-glutamic acid production. Fatty acid ester surfactants and penicillin also induce l-glutamic acid secretion, even in the presence of biotin. However, the mechanism of l-glutamic acid secretion remains unclear. It was recently reported that disruption of odhA, encoding a subunit of the 2-oxoglutarate dehydrogenase complex, resulted in l-gluta...

Glutamate modulation of GABA transport in retinal horizontal cells of the skate

Science.gov (United States)

Kreitzer, Matthew A; Andersen, Kristen A; Malchow, Robert Paul

2003-01-01

Transport of the amino acid GABA into neurons and glia plays a key role in regulating the effects of GABA in the vertebrate retina. We have examined the modulation of GABA-elicited transport currents of retinal horizontal cells by glutamate, the likely neurotransmitter of vertebrate photoreceptors. Enzymatically isolated external horizontal cells of skate were examined using whole-cell voltage-clamp techniques. GABA (1 mm) elicited an inward current that was completely suppressed by the GABA transport inhibitors tiagabine (10 μm) and SKF89976-A (100 μm), but was unaffected by 100 μm picrotoxin. Prior application of 100 μm glutamate significantly reduced the GABA-elicited current. Glutamate depressed the GABA dose-response curve without shifting the curve laterally or altering the voltage dependence of the current. The ionotropic glutamate receptor agonists kainate and AMPA also reduced the GABA-elicited current, and the effects of glutamate and kainate were abolished by the ionotropic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline. NMDA neither elicited a current nor modified the GABA-induced current, and metabotropic glutamate analogues were also without effect. Inhibition of the GABA-elicited current by glutamate and kainate was reduced when extracellular calcium was removed and when recording pipettes contained high concentrations of the calcium chelator BAPTA. Caffeine (5 mm) and thapsigargin (2 nm), agents known to alter intracellular calcium levels, also reduced the GABA-elicited current, but increases in calcium induced by depolarization alone did not. Our data suggest that glutamate regulates GABA transport in retinal horizontal cells through a calcium-dependent process, and imply a close physical relationship between calcium-permeable glutamate receptors and GABA transporters in these cells. PMID:12562999

Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia : A (1)H MRS study

NARCIS (Netherlands)

Curcic-Blake, Branisalava; Bais, Leonie; Sibeijn-Kuiper, Anita; Pijnenborg, Hendrika Maria; Knegtering, Henderikus; Liemburg, Edith; Aleman, André

2017-01-01

Purpose: Glutamatergic models of psychosis propose that dysfunction of N-methyl-D-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory

Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy.

Science.gov (United States)

Choudhury, Sabanum; Borah, Anupom

2015-07-01

Liver diseases lead to a complex syndrome characterized by neurological, neuro-psychiatric and motor complications, called hepatic encephalopathy, which is prevalent in patients and animal models of acute, sub-chronic and chronic liver failure. Although alterations in GABAergic, glutamatergic, cholinergic and serotonergic neuronal functions have been implicated in HE, the molecular mechanisms that lead to HE in chronic liver disease (CLD) is least illustrated. Due to hepatocellular failure, levels of ammonia and homocysteine (Hcy), in addition to others, are found to increase in the brain as well as plasma. Hcy, a non-protein forming amino acid and an excitotoxin, activates ionotropic glutamate (n-methyl-d-aspartate; NMDA) receptors, and thereby leads to influx of Ca(2+) into neurons, which in turn activates several pathways that trigger oxidative stress, inflammation and apoptosis, collectively called excitotoxicity. Elevated levels of Hcy in the plasma and brain, a condition called Hyperhomocysteinemia (HHcy), and the resultant NMDA receptor-mediated excitotoxicity has been implicated in several diseases, including Parkinson's disease and Alzheimer's disease. Although, hyperammonemia has been shown to cause excitotoxicity, the role of HHcy in the development of behavioral and neurochemical alterations that occur in HE has not been illustrated yet. It is hypothesized that CLD-induced HHcy plays a major role in the development of HE through activation of NMDA receptors. It is further hypothesized that HHcy synergizes with hyperammonemia to activate NMDA receptor in the brain, and thereby cause oxidative stress, inflammation and apoptosis, and neuronal loss that leads to HE. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterisation of the expression of NMDA receptors in human astrocytes.

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Ming-Chak Lee

Full Text Available Astrocytes have long been perceived only as structural and supporting cells within the central nervous system (CNS. However, the discovery that these glial cells may potentially express receptors capable of responding to endogenous neurotransmitters has resulted in the need to reassess astrocytic physiology. The aim of the current study was to characterise the expression of NMDA receptors (NMDARs in primary human astrocytes, and investigate their response to physiological and excitotoxic concentrations of the known endogenous NMDAR agonists, glutamate and quinolinic acid (QUIN. Primary cultures of human astrocytes were used to examine expression of these receptors at the mRNA level using RT-PCR and qPCR, and at the protein level using immunocytochemistry. The functionality role of the receptors was assessed using intracellular calcium influx experiments and measuring extracellular lactate dehydrogenase (LDH activity in primary cultures of human astrocytes treated with glutamate and QUIN. We found that all seven currently known NMDAR subunits (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B are expressed in astrocytes, but at different levels. Calcium influx studies revealed that both glutamate and QUIN could activate astrocytic NMDARs, which stimulates Ca2+ influx into the cell and can result in dysfunction and death of astrocytes. Our data also show that the NMDAR ion channel blockers, MK801, and memantine can attenuate glutamate and QUIN mediated cell excitotoxicity. This suggests that the mechanism of glutamate and QUIN gliotoxicity is at least partially mediated by excessive stimulation of NMDARs. The present study is the first to provide definitive evidence for the existence of functional NMDAR expression in human primary astrocytes. This discovery has significant implications for redefining the cellular interaction between glia and neurons in both physiological processes and pathological conditions.

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

Science.gov (United States)

Lelkes, Zoltán; Abdurakhmanova, Shamsiiat; Porkka-Heiskanen, Tarja

2017-09-18

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate. © 2017 European Sleep Research Society.

Investigations into the involvement of NMDA mechanisms in recognition memory.

Science.gov (United States)

Warburton, E Clea; Barker, Gareth R I; Brown, Malcom W

2013-11-01

This review will focus on evidence showing that NMDA receptor neurotransmission is critical for synaptic plasticity processes within brain regions known to be necessary for the formation of object recognition memories. The aim will be to provide evidence concerning NMDA mechanisms related to recognition memory processes and show that recognition memory for objects, places or associations between objects and places depends on NMDA neurotransmission within the perirhinal cortex, temporal association cortex medial prefrontal cortex and hippocampus. Administration of the NMDA antagonist AP5, selectively into each of these brain regions has revealed that the extent of the involvement NMDA receptors appears dependent on the type of information required to solve the recognition memory task; thus NMDA receptors in the perirhinal cortex are crucial for the encoding of long-term recognition memory for objects, and object-in-place associations, but not for short-term recognition memory or for retrieval. In contrast the hippocampus and medial prefrontal cortex are required for both long-term and short-term recognition memory for places or associations between objects and places, or for recognition memory tasks that have a temporal component. Such studies have therefore confirmed that the multiple brain regions make distinct contributions to recognition memory but in addition that more than one synaptic plasticity process must be involved. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Glutamic acid promotes monacolin K production and monacolin K biosynthetic gene cluster expression in Monascus.

Science.gov (United States)

Zhang, Chan; Liang, Jian; Yang, Le; Chai, Shiyuan; Zhang, Chenxi; Sun, Baoguo; Wang, Chengtao

2017-12-01

This study investigated the effects of glutamic acid on production of monacolin K and expression of the monacolin K biosynthetic gene cluster. When Monascus M1 was grown in glutamic medium instead of in the original medium, monacolin K production increased from 48.4 to 215.4 mg l -1 , monacolin K production increased by 3.5 times. Glutamic acid enhanced monacolin K production by upregulating the expression of mokB-mokI; on day 8, the expression level of mokA tended to decrease by Reverse Transcription-polymerase Chain Reaction. Our findings demonstrated that mokA was not a key gene responsible for the quantity of monacolin K production in the presence of glutamic acid. Observation of Monascus mycelium morphology using Scanning Electron Microscope showed glutamic acid significantly increased the content of Monascus mycelium, altered the permeability of Monascus mycelium, enhanced secretion of monacolin K from the cell, and reduced the monacolin K content in Monascus mycelium, thereby enhancing monacolin K production.

Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer's disease: phosphate-activated glutaminase and glutamic acid decarboxylase.

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Burbaeva, G Sh; Boksha, I S; Tereshkina, E B; Savushkina, O K; Prokhorova, T A; Vorobyeva, E A

2014-10-01

Enzymes of glutamate and GABA metabolism in postmortem cerebellum from patients with Alzheimer's disease (AD) have not been comprehensively studied. The present work reports results of original comparative study on levels of phosphate-activated glutaminase (PAG) and glutamic acid decarboxylase isoenzymes (GAD65/67) in autopsied cerebellum samples from AD patients and matched controls (13 cases in each group) as well as summarizes published evidence for altered levels of PAG and GAD65/67 in AD brain. Altered (decreased) levels of these enzymes and changes in links between amounts of these enzymes and other glutamate-metabolizing enzymes (such as glutamate dehydrogenase and glutamine synthetase-like protein) in AD cerebella suggest significantly impaired glutamate and GABA metabolism in this brain region, which was previously regarded as not substantially involved in AD pathogenesis.

[Imbalance of system of glutamin - glutamic acid in the placenta and amniotic fluid at placental insufficiency].

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Pogorelova, T N; Gunko, V O; Linde, V A

2014-01-01

Metabolism of glutamine and glutamic acid has been investigated in the placenta and amniotic fluid under conditions of placental insufficiency. The development of placental insufficiency is characterized by the increased content of glutamic acid and a decrease of glutamine in both placenta and amniotic fluid. These changes changes were accompanied by changes in the activity of enzymes involved in the metabolism of these amino acids. There was a decrease in glutamate dehydrogenase activity and an increase in glutaminase activity with the simultaneous decrease of glutamine synthetase activity. The compensatory decrease in the activity of glutamine keto acid aminotransferase did not prevent a decrease in the glutamine level. The impairments in the system glutamic acid-glutamine were more pronounced during the development of premature labor.

Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

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F. A. Zeiler

2015-01-01

Full Text Available Refractory status epilepticus (RSE and superrefractory status epilepticus (SRSE pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE.

Integrated Analysis of the Transcriptome and Metabolome of Corynebacterium glutamicum during Penicillin-Induced Glutamic Acid Production.

Science.gov (United States)

Hirasawa, Takashi; Saito, Masaki; Yoshikawa, Katsunori; Furusawa, Chikara; Shmizu, Hiroshi

2018-05-01

Corynebacterium glutamicum is known for its ability to produce glutamic acid and has been utilized for the fermentative production of various amino acids. Glutamic acid production in C. glutamicum is induced by penicillin. In this study, the transcriptome and metabolome of C. glutamicum is analyzed to understand the mechanism of penicillin-induced glutamic acid production. Transcriptomic analysis with DNA microarray revealed that expression of some glycolysis- and TCA cycle-related genes, which include those encoding the enzymes involved in conversion of glucose to 2-oxoglutaric acid, is upregulated after penicillin addition. Meanwhile, expression of some TCA cycle-related genes, encoding the enzymes for conversion of 2-oxoglutaric acid to oxaloacetic acid, and the anaplerotic reactions decreased. In addition, expression of NCgl1221 and odhI, encoding proteins involved in glutamic acid excretion and inhibition of the 2-oxoglutarate dehydrogenase, respectively, is upregulated. Functional category enrichment analysis of genes upregulated and downregulated after penicillin addition revealed that genes for signal transduction systems are enriched among upregulated genes, whereas those for energy production and carbohydrate and amino acid metabolisms are enriched among the downregulated genes. As for the metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry, the intracellular content of most metabolites of the glycolysis and the TCA cycle decreased dramatically after penicillin addition. Overall, these results indicate that the cellular metabolism and glutamic acid excretion are mainly optimized at the transcription level during penicillin-induced glutamic acid production by C. glutamicum. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.

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Francesca Calabrese

Full Text Available It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.

Chemical lesioning and glutamate administration reveal a major role for the nucleus tractus solitarius in the cardiac-somatic reflex in rats.

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Liu, X-H; Sun, N; Du, J-Q; Tang, J-S; Han, M; Zhu, J-X; Huo, F-Q

2012-04-05

Many patients suffer from secondary muscle hyperalgesia after experiencing angina pectoris. In this study, we examined the role of the nucleus tractus solitarius (NTS) and glutamate receptors in modulating cardiac-evoked muscle hyperalgesia induced by pericardial capsaicin, which was monitored by recording electromyogram (EMG) activity from the spinotrapezius muscle in the anesthetized rat. Unilateral chemical lesioning of the commissural NTS with the neurotoxin ibotenic acid significantly depressed the cardiac-somatic reflex; the EMG responses decreased to 56.4 ± 6.9% of that of the controls (5 of 5). Microinjection of the excitatory amino acid glutamate, at 10, 20, and 50 nmol, into the commissural NTS increased the EMG response, in a dose-dependent manner, to 116.9 ± 4.9%, 143.9 ± 10.2%, and 214.2 ± 15.8% (n=8), respectively, of that of the controls. In contrast, microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a, d]-cyclohepten-5,10-imine maleate (MK-801) at 4 and 6 nmol, decreased the EMG response to 45.2 ± 10.6% and 36.8 ± 14.3%, respectively, of that of the controls (n=8 for each dose). Similarly, the metabotropic glutamate receptor (mGluR) antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG), at 2.5 and 5 nmol, decreased the EMG response to 65.2 ± 16.3% and 57.0 ± 4.2%, respectively, of that of the controls. When a combination of MK-801 and MCPG was administrated, the EMG response further decreased to 22.5 ± 13.2% (n=6) of that of the controls. However, administration of a non-NMDA receptor antagonist 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), at 2 and 5 nmol, had no effect on the EMG response. These results suggest that the NTS is involved in the facilitation of the cardiac-somatic reflex, and that the NMDA receptor and mGluRs play an important role in mediating this effect. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Sequential enzymatic synthesis and separation of 13N-L-glutamic acid and 13N-L-alanine

International Nuclear Information System (INIS)

Cohen, M.B.; Spolter, L.; MacDonald, M.; Chang, C.C.; Takahashi, J.

1975-01-01

The sequential enzymatic synthesis and separation of 13 N-L-glutamic acid and 13 N-L-alanine are described. Basically, that involves the synthesis of 13 N-L-glutamic acid by one enzyme, the transamination of the labeled glutamic acid to form 13 N-L-alanine by a second enzyme, and the separation of the two amino acids by rapid column chromatography. The 13 N-L-alanine was evaluated in animals by imaging and tissue distribution studies and showed good potential as a pancreatic imaging agent

Elevated systemic glutamic acid level in the non-obese diabetic mouse is Idd linked and induces beta cell apoptosis.

Science.gov (United States)

Banday, Viqar Showkat; Lejon, Kristina

2017-02-01

Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F 2 cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2 -/- Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy. © 2016 John Wiley & Sons Ltd.

Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus.

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Xie, Meilan; Yan, Jie; He, Chao; Yang, Li; Tan, Gang; Li, Chao; Hu, Zhian; Wang, Jiali

2015-06-01

Hippocampus-dependent learning memory is sensitive to sleep deprivation (SD). Although the ionotropic glutamate receptors play a vital role in synaptic plasticity and learning and memory, however, whether the expression of these receptor subunits is modulated by sleep loss remains unclear. In the present study, western blotting was performed by probing with specific antibodies against the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, GluA2, GluA3, and against the N-methyl-d-aspartate (NMDA) glutamate receptor subunits GluN1, GluN2A, GluN2B. In hippocampus, down regulation of surface GluA1 and GluN2A surface expression were observed in both SD groups. However, surface expression level of GluA2, GluA3, GluN1 and GluN2B was significantly up-regulated in 8h-SD rats when compared to the 4h-SD rats. In parallel with the complex changes in AMPA and NMDA receptor subunit expressions, we found the 8h-SD impaired rat spatial working memory in 30-s-delay T-maze task, whereas no impairment of spatial learning was observed in 4h-SD rats. These results indicate that sleep loss alters the relative expression levels of the AMPA and NMDA receptors, thus affects the synaptic strength and capacity for plasticity and partially contributes to spatial memory impairment. Copyright © 2015. Published by Elsevier B.V.

Adsorption of Amino Acids and Glutamic Acid-Based Surfactants on Imogolite Clays.

Science.gov (United States)

Bonini, Massimo; Gabbani, Alessio; Del Buffa, Stefano; Ridi, Francesca; Baglioni, Piero; Bordes, Romain; Holmberg, Krister

2017-03-07

Aluminum oxide surfaces are of utmost interest in different biotech applications, in particular for their use as adjuvants (i.e., booster of the immune response against infectious agents in vaccines production). In this framework, imogolite clays combine the chemical flexibility of an exposed alumina surface with 1D nanostructure. This work reports on the interaction between amino acids and imogolite, using turbidimetry, ζ-potential measurements, and Fourier transform infrared spectroscopy as main characterization tools. Amino acids with different side chain functional groups were investigated, showing that glutamic acid (Glu) has the strongest affinity for the imogolite surface. This was exploited to prepare a composite material made of a synthetic surfactant bearing a Glu polar head and a hydrophobic C 12 alkyl tail, adsorbed onto the surface of imogolite. The adsorption of a model drug (rhodamine B isothiocyanate) by the hybrid was evaluated both in water and in physiological saline conditions. The findings of this paper suggest that the combination between the glutamate headgroup and imogolite represents a promising platform for the fabrication of hybrid nanostructures with tailored functionalities.

Exogenous glutamate induces short and long-term potentiation in the rat medial vestibular nuclei.

Science.gov (United States)

Grassi, S; Frondaroli, A; Pessia, M; Pettorossi, V E

2001-08-08

In rat brain stem slices, high concentrations of exogenous glutamate induce long-term potentiation (LTP) of the field potentials evoked in the medial vestibular nuclei (MVN) by vestibular afferent stimulation. At low concentrations, glutamate can also induce short-term potentiation (STP), indicating that LTP and STP are separate events depending on the level of glutamatergic synapse activation. LTP and STP are prevented by blocking NMDA receptors and nitric oxide (NO) synthesis. Conversely, blocking platelet-activating factor (PAF) and group I metabotropic glutamate receptors only prevents the full development of LTP. Moreover, in the presence of blocking agents, glutamate causes transient inhibition, suggesting that when potentiation is impeded, exogenous glutamate can activate presynaptic mechanisms that reduce glutamate release.

Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.

Science.gov (United States)

De Sarro, Giovambattista; Chimirri, Alba; Meldrum, Brian S

2002-09-06

We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade. Copyright 2002 Elsevier Science B.V.

Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity

International Nuclear Information System (INIS)

Cattani, Daiane; Oliveira Cavalli, Liz Vera Lúcia de; Heinz Rieg, Carla Elise; Domingues, Juliana Tonietto; Dal-Cim, Tharine; Tasca, Carla Inês; Mena Barreto Silva, Fátima Regina; Zamoner, Ariane

2014-01-01

Graphical abstract: - Highlights: • Roundup ® induces Ca 2+ influx through L-VDCC and NMDA receptor activation. • The mechanisms underlying Roundup ® neurotoxicity involve glutamatergic excitotoxicity. • Kinase pathways participate in Roundup ® -induced neural toxicity. • Roundup ® alters glutamate uptake, release and metabolism in hippocampal cells. - Abstract: Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup ® (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30 min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup ® (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup ® (0.00005–0.1%) during 30 min and experiments were carried out to determine whether glyphosate affects 45 Ca 2+ influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, 14 C-α-methyl-amino-isobutyric acid ( 14 C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup ® (30 min) increases 45 Ca 2+ influx by activating NMDA receptors and voltage-dependent Ca 2+ channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup ® -induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup ® increased 3 H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup ® decreased 3 H-glutamate uptake and

Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats.

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Potapenko, Evgeniy S; Biancardi, Vinicia C; Zhou, Yiqiang; Stern, Javier E

2012-08-01

Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

Oxytocin induces penile erection and yawning when injected into the bed nucleus of the stria terminalis: Involvement of glutamic acid, dopamine, and nitric oxide.

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Sanna, Fabrizio; Bratzu, Jessica; Argiolas, Antonio; Melis, Maria Rosaria

2017-11-01

Oxytocin (5-100ng), but not Arg 8 -vasopressin (100ng), injected unilaterally into the bed nucleus of the stria terminalis (BNST) induces penile erection and yawning in a dose-dependent manner in male rats. The minimal effective dose was 20ng for penile erection and 5ng for yawning. Oxytocin responses were abolished not only by the oxytocin receptor antagonist d(CH 2 ) 5 Tyr(Me) 2 -Orn 8 -vasotocin (1μg), but also by (+) MK-801 (1μg), an excitatory amino acid receptor antagonist of the N-methyl-d-aspartic acid (NMDA) subtype, SCH 23390 (1μg), a D1 receptor antagonist, but not haloperidol (1μg), a D2 receptor antagonist, and SMTC (40μg), an inhibitor of neuronal nitric oxide synthase, injected into the BNST 15min before oxytocin. Oxytocin-induced penile erection, but not yawning, was also abolished by CNQX (1μg), an excitatory amino acid receptor antagonist of the AMPA subtype. In contrast, oxytocin responses were not reduced by bicuculline (20ng), a GABA A receptor antagonist, phaclofen (5μg), a GABA B receptor antagonist, CP 376395, a CRF receptor-1 antagonist (5μg), or astressin 2B, a CRF receptor-2 antagonist (150ng). Considering the ability of NMDA (100ng) to induce penile erection and yawning when injected into the BNST and the available evidence showing possible interaction among oxytocin, glutamic acid, and dopamine in the BNST, oxytocin possibly activates glutamatergic neurotransmission in the BNST. This in turn leads to the activation of neural pathways projecting back to the paraventricular nucleus, medial preoptic area, ventral tegmental area, and/or ventral subiculum/amygdala, thereby inducing penile erection and yawning. Copyright © 2017 Elsevier Inc. All rights reserved.

Determination of glutamine and glutamic acid in mammalian cell cultures using tetrathiafulvalene modified enzyme electrodes.

Science.gov (United States)

Mulchandani, A; Bassi, A S

1996-01-01

Tetrathiafulvalene (TTF) mediated amperometric enzyme electrodes have been developed for the monitoring of L-glutamine and L-glutamic acid in growing mammalian cell cultures. The detection of glutamine was accomplished by a coupled enzyme system comprised of glutaminase plus glutamate oxidase, while the detection of glutamic acid was carried out by a single enzyme, glutamate oxidase. The appropriate enzyme(s) were immoblized on the Triton-X treated surface of tetrathiafulvalene modified carbon paste electrodes by adsorption, in conjunction with entrapment by an electrochemically deposited copolymer film of 1,3-phenylenediamine and resorcinol. Operating conditions for the glutamine enzyme electrode were optimized with respect to the amount of enzymes immoblized, pH, temperature and mobile phase flow rate for operation in a flow injection (FIA) system. When applied to glutamine and glutamic acid measurements in mammalian cell culture in FIA, the results obtained with enzyme electrodes were in excellent agreement with those determined by enzymatic analysis.

Examining the role of glutamic acid 183 in chloroperoxidase catalysis

NARCIS (Netherlands)

Yi, X.; Conesa, A.; Punt, P.J.; Hager, L.P.

2003-01-01

Site-directed mutagenesis has been used to investigate the role of glutamic acid 183 in chloroperoxidase catalysis. Based on the x-ray crystallographic structure of chloroperoxidase, Glu-183 is postulated to function on distal side of the heme prosthetic group as an acid-base catalyst in

Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid

DEFF Research Database (Denmark)

Conti, P; De Amici, M; Bräuner-Osborne, Hans

2002-01-01

The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino......-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic...... acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate...

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

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Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

2015-08-15

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Enhanced production of poly glutamic acid by Bacillus sp. SW1-2 ...

African Journals Online (AJOL)

Bacillus sp. SW1-2 producing poly glutamic acid (PGA), locally isolated from Eastern province in Saudi Arabia, was characterized and identified based on 16S rRNA gene sequencing. Phylogenetic analysis revealed its closeness to Bacillus megaterium. The homopolymer consists mainly of glutamic as indicated in the ...

The effect of chronic ethanol on glutamate binding in human and rat brain

International Nuclear Information System (INIS)

Cummins, J.T.; Sack, M.; von Hungen, K.

1990-01-01

Quantitative autoradiographic techniques demonstrate that chronic alcohol administration causes a decrease in [ 3 H]-glutamate binding to hippocampal N-methyl-D-aspartate (NMDA) receptors. A 14% decrease in [ 3 H]-glutamate binding in the hippocampal CA 1 region is seen both in the rat after five days of ethanol administration and in postmortem hippocampal tissues from alcoholics. In the rat, 24 hr ethanol withdrawal values are intermediate between control and alcohol binding levels. There was no significant effect of ethanol on [ 3 H]-glutamate binding in the cortex or caudate

Selective increases of AMPA, NMDA and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics

Directory of Open Access Journals (Sweden)

Zhe eJin

2014-01-01

Full Text Available Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG, orbitofrontal cortex (OFC, and dorso-lateral prefrontal cortex (DL-PFC samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-ylpropanoic acid receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate receptor subunits GluN1, GluN2A, GluN2C, GluN2D and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011. Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

Analysis of L-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli.

Science.gov (United States)

Nishio, Yousuke; Ogishima, Soichi; Ichikawa, Masao; Yamada, Yohei; Usuda, Yoshihiro; Masuda, Tadashi; Tanaka, Hiroshi

2013-09-22

Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature-based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental cell growth profile of fed-batch cultivation in jar fermenters. However, to confirm the biological appropriateness of our model, sensitivity analysis and experimental validation were required. We constructed an L-glutamic acid fermentation simulation model by removing sucAB, a gene encoding α-ketoglutarate dehydrogenase. We then performed systematic sensitivity analysis for L-glutamic acid production; the results of this process corresponded with previous experimental data regarding L-glutamic acid fermentation. Furthermore, it allowed us to predicted the possibility that accumulation of 3-phosphoglycerate in the cell would regulate the carbon flux into the TCA cycle and lead to an increase in the yield of L-glutamic acid via fermentation. We validated this hypothesis through a fermentation experiment involving a model L-glutamic acid-production strain, E. coli MG1655 ΔsucA in which the phosphoglycerate kinase gene had been amplified to cause accumulation of 3-phosphoglycerate. The observed increase in L-glutamic acid production verified the biologically meaningful predictive power of our dynamic metabolic simulation model. In this study, dynamic simulation using a literature-based model was shown to be useful for elucidating the precise mechanisms involved in fermentation processes inside the cell. Further exhaustive sensitivity analysis will facilitate identification of novel factors involved in the metabolic regulation of amino acid fermentation.

Prostaglandin E(2) stimulates glutamate receptor-dependent astrocyte neuromodulation in cultured hippocampal cells.

Science.gov (United States)

Sanzgiri, R P; Araque, A; Haydon, P G

1999-11-05

Recent Ca(2+) imaging studies in cell culture and in situ have shown that Ca(2+) elevations in astrocytes stimulate glutamate release and increase neuronal Ca(2+) levels, and that this astrocyte-neuron signaling can be stimulated by prostaglandin E(2) (PGE(2)). We investigated the electrophysiological consequences of the PGE(2)-mediated astrocyte-neuron signaling using whole-cell recordings on cultured rat hippocampal cells. Focal application of PGE(2) to astrocytes evoked a Ca(2+) elevation in the stimulated cell by mobilizing internal Ca(2+) stores, which further propagated as a Ca(2+) wave to neighboring astrocytes. Whole-cell recordings from neurons revealed that PGE(2) evoked a slow inward current in neurons adjacent to astrocytes. This neuronal response required the presence of an astrocyte Ca(2+) wave and was mediated through both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors. Taken together with previous studies, these data demonstrate that PGE(2)-evoked Ca(2+) elevations in astrocyte cause the release of glutamate which activates neuronal ionotropic receptors. Copyright 1999 John Wiley & Sons, Inc.

Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

Science.gov (United States)

Woda, Alain; Blanc, Olivier; Voisin, Daniel L; Coste, Jérôme; Molat, Jean-Louis; Luccarini, Philippe

2004-04-01

Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19). These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.

Mechanical, thermal and morphological properties of glutaraldehyde crosslinked bovine pericardium followed by glutamic acid treatment

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Gilberto Goissis

2009-03-01

Full Text Available Major problems with valve bioprostheses are associated with progressive structural deterioration and calcification, directly associated with the use of glutaraldehyde (GA. This work describes the effects of GA processing and borate/glutamic acid buffer treatment on the mechanical, thermal and morphological properties of 0.5% GA crosslinked bovine pericardium (BP. The results showed that while the treatment of 0.5% GA crosslinked BP with borate/glutamic acid significantly improves the mechanical properties, it had no visible effect on surface morphology. Better surface preservation was only achieved for BP pre-treated with a lower GA concentration followed by the conventional treatment (0.5% GA. Improvements in mechanical properties probably arises from structural changes probably involving the depolymerization of polymeric GA crosslinks and an increase electrostatic interaction due to covalent binding of glutamic acid to free carbonyl groups (Schiff base.The results indicate that the treatment GA crosslinked BP with borate/glutamic acid buffer may be an attractive procedure for the manufacture of heart valve bioprostheses.

Glutamate oxidation in astrocytes: Roles of glutamate dehydrogenase and aminotransferases

DEFF Research Database (Denmark)

McKenna, Mary C; Stridh, Malin H; McNair, Laura Frendrup

2016-01-01

to the presynaptic neurons as the nonexcitatory amino acid glutamine. The cycle was initially thought to function with a 1:1 ratio between glutamate released and glutamine taken up by neurons. However, studies of glutamate metabolism in astrocytes have shown that a considerable proportion of glutamate undergoes...... the enzymes that mediate this conversion. Methods include pharmacological tools such as the transaminase inhibitor aminooxyacetic acid, studies using GDH knockout mice, and siRNA-mediated knockdown of GDH in astrocytes. Studies in brain slices incubated with [15N]glutamate demonstrated activity of GDH......The cellular distribution of transporters and enzymes related to glutamate metabolism led to the concept of the glutamate–glutamine cycle. Glutamate is released as a neurotransmitter and taken up primarily by astrocytes ensheathing the synapses. The glutamate carbon skeleton is transferred back...

Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue

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N.M. Jadavji

2015-06-01

Full Text Available Methylenetetrahydrofolate reductase (MTHFR is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM. In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT, which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and γ-aminobutyric acid in within the cerebellum and hippocampus. Mthfr−/− mice had reduced levels of glutamate in the amygdala and γ-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and γ-aminobutyric acid.

Synthesis and Characterization of Chromium (III) Complexes with L-Glutamic Acid, Glycine and LCysteine

OpenAIRE

Kun Sri Budiasih; Chairil Anwar; Sri Juari Santosa; Hilda Ismail

2013-01-01

Some Chromium (III) complexes were synthesized with three amino acids: L Glutamic Acid, Glycine, and L-cysteine as the ligands, in order to provide a new supplement containing Cr(III) for patients with type 2 diabetes mellitus. The complexes have been prepared by refluxing a mixture of Chromium(III) chloride in aqueous solution with L-glutamic acid, Glycine, and L-cysteine after pH adjustment by sodium hydroxide. These complexes were characterized by Infrared and Uv-Vis s...

Vulnerability to omega-3 deprivation in a mouse model of NMDA receptor hypofunction.

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Islam, Rehnuma; Trépanier, Marc-Olivier; Milenkovic, Marija; Horsfall, Wendy; Salahpour, Ali; Bazinet, Richard P; Ramsey, Amy J

2017-01-01

Several studies have found decreased levels of ω-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary ω-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of ω-3, either depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of ω-6 fatty acids regardless of their diet. While ω-3 supplementation did not improve any of the NR1KD behavioral abnormalities, ω-3 depletion exacerbated their deficits in executive function. Omega-3 depletion also caused extreme mortality among male mutant mice, with 75% mortality rate by 12 weeks of age. Our studies show that alterations in NMDAR function alter serum and brain lipid composition and make the brain more vulnerable to dietary ω-3 deprivation.

Glutamic acid production from wheat by-products using enzymatic and acid hydrolysis

NARCIS (Netherlands)

Sari, Y.W.; Alting, A.C.; Floris, R.; Sanders, J.P.M.; Bruins, M.E.

2014-01-01

Glutamic acid (Glu) has potential as feedstock for bulk chemicals production. It has also been listed as one of the top twelve chemicals derived from biomass. Large amounts of cheaper Glu can be made available by enabling its production from biomass by-products, such as wheat dried distillers grains

The effects of reactants ratios, reaction temperatures and times on Maillard reaction products of the L-ascorbic acid/L-glutamic acid system

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Yong-Yan ZHOU

2016-01-01

Full Text Available Abstract The transformation law of the Maillard reaction products with three different reactants ratios - equimolar reactants, excess L-glutamic acid and excess L-ascorbic acid reaction respectively, five different temperatures, and different time conditions for the L-ascorbic acid / L-glutamic acid system were investigated. Results showed that, the increase of the reaction time and temperature led to the increase of the browning products, uncoloured intermediate products, as well as aroma compounds. Compared with the equimolar reaction system, the excess L-ascorbic acid reaction system produced more browning products and uncoloured intermediate products, while the aroma compounds production remained the same. In the excess L-glutamic acid system, the uncoloured intermediate products increased slightly, the browning products remained the same, while the aroma compounds increased.

Analysis of l-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli

Science.gov (United States)

2013-01-01

Background Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature-based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental cell growth profile of fed-batch cultivation in jar fermenters. However, to confirm the biological appropriateness of our model, sensitivity analysis and experimental validation were required. Results We constructed an l-glutamic acid fermentation simulation model by removing sucAB, a gene encoding α-ketoglutarate dehydrogenase. We then performed systematic sensitivity analysis for l-glutamic acid production; the results of this process corresponded with previous experimental data regarding l-glutamic acid fermentation. Furthermore, it allowed us to predicted the possibility that accumulation of 3-phosphoglycerate in the cell would regulate the carbon flux into the TCA cycle and lead to an increase in the yield of l-glutamic acid via fermentation. We validated this hypothesis through a fermentation experiment involving a model l-glutamic acid-production strain, E. coli MG1655 ΔsucA in which the phosphoglycerate kinase gene had been amplified to cause accumulation of 3-phosphoglycerate. The observed increase in l-glutamic acid production verified the biologically meaningful predictive power of our dynamic metabolic simulation model. Conclusions In this study, dynamic simulation using a literature-based model was shown to be useful for elucidating the precise mechanisms involved in fermentation processes inside the cell. Further exhaustive sensitivity analysis will facilitate identification of novel factors involved in the metabolic regulation of amino acid fermentation. PMID

Bioconversion of l-glutamic acid to α-ketoglutaric acid by an immobilized whole-cell biocatalyst expressing l-amino acid deaminase from Proteus mirabilis.

Science.gov (United States)

Hossain, Gazi Sakir; Li, Jianghua; Shin, Hyun-dong; Chen, Rachel R; Du, Guocheng; Liu, Long; Chen, Jian

2014-01-01

The goal of this work was to develop an immobilized whole-cell biocatalytic process for the environment-friendly synthesis of α-ketoglutaric acid (α-KG) from l-glutamic acid. We compared the suitability of Escherichia coli and Bacillus subtilis strains overexpressing Proteus mirabilisl-amino acid deaminase (l-AAD) as potential biocatalysts. Although both recombinant strains were biocatalytically active, the performance of B. subtilis was superior to that of E. coli. With l-glutamic acid as the substrate, α-KG production levels by membranes isolated from B. subtilis and E. coli were 55.3±1.73 and 21.7±0.39μg/mg protein/min, respectively. The maximal conversion ratio of l-glutamic acid to α-KG was 31% (w/w) under the following optimal conditions: 15g/L l-glutamic acid, 20g/L whole-cell biocatalyst, 5mM MgCl2, 40°C, pH 8.0, and 24-h incubation. Immobilization of whole cells with alginate increased the recyclability by an average of 23.33% per cycle. This work established an efficient one-step biotransformation process for the production of α-KG using immobilized whole B. subtilis overexpressing P. mirabilisl-AAD. Compared with traditional multistep chemical synthesis, the biocatalytic process described here has the advantage of reducing environmental pollution and thus has great potential for the large-scale production of α-KG. Copyright © 2013 Elsevier B.V. All rights reserved.

Excitatory amino acids in epilepsy and potential novel therapies.

Science.gov (United States)

Meldrum, B S

1992-07-01

Evidence that an abnormality of excitatory neurotransmission may contribute to the epileptic phenomena in various animal and human syndromes is reviewed. Altered glutamate transport or metabolism may be a contributory factor in some genetic syndromes and enhanced responsiveness to activation of NMDA receptors may be significant in various acquired forms of epilepsy. Decreasing glutamatergic neurotransmission provides a rational therapeutic approach to epilepsy. Potent anticonvulsant effects are seen with the acute administration of NMDA antagonists in a wide range of animal models. Some competitive antagonists acting at the NMDA/glutamate site show prolonged anticonvulsant activity following oral administration at doses free of motor side effects and appear suitable for clinical trial.

The selective conversion of glutamic acid in amino acid mixtures using glutamate decarboxylase--a means of separating amino acids for synthesizing biobased chemicals.

Science.gov (United States)

Teng, Yinglai; Scott, Elinor L; Sanders, Johan P M

2014-01-01

Amino acids (AAs) derived from hydrolysis of protein rest streams are interesting feedstocks for the chemical industry due to their functionality. However, separation of AAs is required before they can be used for further applications. Electrodialysis may be applied to separate AAs, but its efficiency is limited when separating AAs with similar isoelectric points. To aid the separation, specific conversion of an AA to a useful product with different charge behavior to the remaining compounds is desired. Here the separation of L-aspartic acid (Asp) and L-glutamic acid (Glu) was studied. L-Glutamate α-decarboxylase (GAD, Type I, EC 4.1.1.15) was applied to specifically convert Glu into γ-aminobutyric acid (GABA). GABA has a different charge behavior from Asp therefore allowing a potential separation by electrodialysis. Competitive inhibition and reduced operational stability caused by Asp could be eliminated by maintaining a sufficiently high concentration of Glu. Immobilization of GAD does not reduce the enzyme's initial activity. However, the operational stability was slightly reduced. An initial study on the reaction operating in a continuous mode was performed using a column reactor packed with immobilized GAD. As the reaction mixture was only passed once through the reactor, the conversion of Glu was lower than expected. To complete the conversion of Glu, the stream containing Asp and unreacted Glu might be recirculated back to the reactor after GABA has been removed. Overall, the reaction by GAD is specific to Glu and can be applied to aid the electrodialysis separation of Asp and Glu. © 2014 American Institute of Chemical Engineers.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

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Cunha, Andréia S; Matheus, Filipe C; Moretti, Morgana; Sampaio, Tuane B; Poli, Anicleto; Santos, Danúbia B; Colle, Dirleise; Cunha, Mauricio P; Blum-Silva, Carlos H; Sandjo, Louis P; Reginatto, Flávio H; Rodrigues, Ana Lúcia S; Farina, Marcelo; Prediger, Rui D

2016-10-01

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice

Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: A potential mechanism for the anticonvulsive effects

OpenAIRE

Feng, Yangzheng; LeBlanc, Michael H.; Regunathan, Soundar

2005-01-01

Glutamate has been implicated in the initiation and spread of seizure activity. Agmatine, an endogenous neuromodulator, is an antagonist of NMDA receptors and has anticonvulsive effects. Whether agmatine regulate glutamate release, as measured by in vivo microdialysis, is not known. In this study, we used pentylenetetrazole (PTZ)-induced seizure model to determine the effect of agmatine on extracellular glutamate in rat brain. We also determined the time course and the amount of agmatine that...

Structure-activity relationship of daptomycin analogues with substitution at (2S, 3R) 3-methyl glutamic acid position.

Science.gov (United States)

Lin, Du'an; Lam, Hiu Yung; Han, Wenbo; Cotroneo, Nicole; Pandya, Bhaumik A; Li, Xuechen

2017-02-01

Daptomycin is a highly effective lipopeptide antibiotic against Gram-positive pathogens. The presence of (2S, 3R) 3-methyl glutamic acid (mGlu) in daptomycin has been found to be important to the antibacterial activity. However the role of (2S, 3R) mGlu is yet to be revealed. Herein, we reported the syntheses of three daptomycin analogues with (2S, 3R) mGlu substituted by (2S, 3R) methyl glutamine (mGln), dimethyl glutamic acid and (2S, 3R) ethyl glutamic acid (eGlu), respectively, and their antibacterial activities. The detailed synthesis of dimethyl glutamic acid was also reported. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhancing poly-γ-glutamic acid production in Bacillus amyloliquefaciens by introducing the glutamate synthesis features from Corynebacterium glutamicum.

Science.gov (United States)

Feng, Jun; Quan, Yufen; Gu, Yanyan; Liu, Fenghong; Huang, Xiaozhong; Shen, Haosheng; Dang, Yulei; Cao, Mingfeng; Gao, Weixia; Lu, Xiaoyun; Wang, Yi; Song, Cunjiang; Wang, Shufang

2017-05-22

Poly-γ-glutamic acid (γ-PGA) is a valuable polymer with glutamate as its sole precursor. Enhancement of the intracellular glutamate synthesis is a very important strategy for the improvement of γ-PGA production, especially for those glutamate-independent γ-PGA producing strains. Corynebacterium glutamicum has long been used for industrial glutamate production and it exhibits some unique features for glutamate synthesis; therefore introduction of these metabolic characters into the γ-PGA producing strain might lead to increased intracellular glutamate availability, and thus ultimate γ-PGA production. In this study, the unique glutamate synthesis features from C. glutamicum was introduced into the glutamate-independent γ-PGA producing Bacillus amyloliquefaciens NK-1 strain. After introducing the energy-saving NADPH-dependent glutamate dehydrogenase (NADPH-GDH) pathway, the NK-1 (pHT315-gdh) strain showed slightly increase (by 9.1%) in γ-PGA production. Moreover, an optimized metabolic toggle switch for controlling the expression of ɑ-oxoglutarate dehydrogenase complex (ODHC) was introduced into the NK-1 strain, because it was previously shown that the ODHC in C. glutamicum was completely inhibited when glutamate was actively produced. The obtained NK-PO1 (pHT01-xylR) strain showed 66.2% higher γ-PGA production than the NK-1 strain. However, the further combination of these two strategies (introducing both NADPH-GDH pathway and the metabolic toggle switch) did not lead to further increase of γ-PGA production but rather the resultant γ-PGA production was even lower than that in the NK-1 strain. We proposed new metabolic engineering strategies to improve the γ-PGA production in B. amyloliquefaciens. The NK-1 (pHT315-gdh) strain with the introduction of NADPH-GDH pathway showed 9.1% improvement in γ-PGA production. The NK-PO1 (pHT01-xylR) strain with the introduction of a metabolic toggle switch for controlling the expression of ODHC showed 66.2% higher �

Role of astrocytes in depolarization-coupled release of glutamate in cerebellar cultures

DEFF Research Database (Denmark)

Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

2004-01-01

Release of preloaded D-[3H]aspartate in response to depolarization induced by high potassium, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or the endogenous agonist glutamate was studied using cultured glutamatergic cerebellar granule neurons, cerebell...

Intracellular Na+ concentration influences short-term plasticity of glutamate transporter-mediated currents in neocortical astrocytes.

Science.gov (United States)

Unichenko, Petr; Myakhar, Olga; Kirischuk, Sergei

2012-04-01

Fast synaptic transmission requires a rapid clearance of the released neurotransmitter from the extracellular space. Glial glutamate transporters (excitatory amino acid transporters, EAATs) strongly contribute to glutamate removal. In this work, we investigated the paired-pulse plasticity of synaptically activated, glutamate transporter-mediated currents (STCs) in cortical layer 2/3 astrocytes. STCs were elicited by local electrical stimulation in layer 4 in the presence of ionotropic glutamate (AMPA and NMDA), GABAA, and GABAB receptor antagonists. In experiments with low [Na(+)]i (5 mM) intrapipette solution, STCs elicited by paired-pulse stimulation demonstrated paired-pulse facilitation (PPF) at short (astrocytic [Na(+)]i, reduced the mean STC amplitude, decreased PPF at short ISIs, and slowed STC kinetics. All GABA-induced changes were blocked by NO-711 and SNAP-5114, GABA transporter (GATs) antagonists. In experiments with the low intrapipette solution, GAT blockade under control conditions decreased PPF at short ISIs both at room and at near physiological temperatures. Dialysis of single astrocyte with low [Na(+)]i solution increased the amplitude and reduced PPR of evoked field potentials recorded in the vicinity of the astrocyte. We conclude that (1) endogenous GABA via GATs may influence EAAT functioning and (2) astrocytic [Na(+)]i modulates the short-term plasticity of STCs and in turn the efficacy of glutamate removal. Copyright © 2012 Wiley Periodicals, Inc.

PRODUCTION AND PURIFICATION OF IgY ANTIBODIES AS A NOVEL TOOL TO PURIFY THE NR1 SUBUNIT OF NMDA RECEPTO

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Edgar Antonio Reyes Montaño

2011-12-01

Full Text Available Producing polyclonal antibodies (IgY inchickens has advantages over those obtainedin other animal models, since theyhave been used as a tool for studyingdifferent proteins (NMDA glutamate receptorin our case, specifically the NR1subunit. We produced specific antibodiesagainst expression products by thealternative splicing of the gene encodingNMDA receptor NR1 subunit in adult ratbrain. Three peptides corresponding tothe splicing sites (N1, C1 and C2’ cassetteswere designed, synthesised and usedindividually as antigens in hens. Specificimmunoglobulins were purified fromyolks. The antibodies were then used forpurifying the NMDA receptor NR1 subunitusing affinity chromatography couplingthe three antibodies to the support.R

Preliminary studies of 99mTc-memantine derivatives for NMDA receptor imaging

International Nuclear Information System (INIS)

Zhou Xingqin; Zhang Jiankang; Yan Chenglong; Cao Guoxian; Zhang Rongjun; Cai Gangming; Jiang Mengjun; Wang Songpei

2012-01-01

Introduction: Novel technetium-labeled ligands, 99m Tc-NCAM and 99m Tc-NHAM were developed from the N-methyl-D-aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N 2 S 2 . This study evaluated the binding affinity and specificity of the ligands for the NMDA receptor. Methods: Ligand biodistribution and uptake specificity in the brain were investigated in mice. Binding affinity and specificity were determined by radioligand receptor binding assay. Three antagonists were used for competitive binding analysis. In addition, uptake of the complexes into SH-SY5Y nerve cells was evaluated. Results: The radiochemical purity of 99m Tc-labeled ligands was more than 95%. Analysis of brain regional uptake showed higher concentration in the frontal lobe and specific uptake in the hippocampus. 99m Tc-NCAM reached a higher target to nontarget ratio than 99m Tc-NHAM. The results indicated that 99m Tc-NCAM bound to a single site on the NMDA receptor with a K d of 701.21 nmol/l and a B max of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D 2 and 5HT 1A receptor partial agonist aripiprazole, inhibited specific binding of 99m Tc-NCAM to the NMDA receptor. Cell physiology experiments showed that NCAM can increase the viability of SH-SY5Y cells after glutamate-induced injury. Conclusions: The new radioligand 99m Tc-NCAM has good affinity for and specific binding to the NMDA receptor, and easily crosses the blood–brain barrier; suggesting that it might be a potentially useful tracer for NMDA receptor expression.

Differential Modulation of GABAA and NMDA Receptors by an α7-nicotinic Acetylcholine Receptor Agonist in Chronic Glaucoma

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Xujiao Zhou

2017-12-01

Full Text Available Presynaptic modulation of γ-aminobutyric acid (GABA release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR agonist promotes retinal ganglion cell (RGC survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. In this study, we investigated GABAA and N-methyl-D-aspartate (NMDA receptor activity in control and glaucomatous retinal slices and the regulation of amino acid receptor expression and function by α7-nAChR. Whole-cell patch-clamp recordings from RGCs revealed that the α7-nAChR specific agonist PNU-282987 enhanced the amplitude of currents elicited by GABA and reduced the amplitude of currents elicited by NMDA. The positive modulation of GABAA receptor and the negative modulation of NMDA receptor (NMDAR by PNU-282987-evoked were prevented by pre-administration of the α7-nAChR antagonist methyllycaconitine (MLA. The frequency and the amplitude of glutamate receptor-mediated miniature glutamatergic excitatory postsynaptic currents (mEPSCs were not significantly different between the control and glaucomatous RGCs. Additionally, PNU-282987-treated slices showed no alteration in the frequency or amplitude of mEPSCs relative to control RGCs. Moreover, we showed that expression of the α1 subunit of the GABAA receptor was downregulated and the expression of the NMDAR NR2B subunit was upregulated by intraocular pressure (IOP elevation, and the changes of high IOP were blocked by PNU-282987. In conclusion, retina GABAA and NMDARs are modulated positively and negatively, respectively, by activation of α7-nAChR in in vivo chronic glaucomatous models.

Identification and quantitation of new glutamic acid derivatives in soy sauce by UPLC/MS/MS.

Science.gov (United States)

Frerot, Eric; Chen, Ting

2013-10-01

Glutamic acid is an abundant amino acid that lends a characteristic umami taste to foods. In fermented foods, glutamic acid can be found as a free amino acid formed by proteolysis or as a non-proteolytic derivative formed by microorganisms. The aim of the present study was to identify different structures of glutamic acid derivatives in a typical fermented protein-based food product, soy sauce. An acidic fraction was prepared with anion-exchange solid-phase extraction (SPE) and analyzed by UPLC/MS/MS and UPLC/TOF-MS. α-Glutamyl, γ-glutamyl, and pyroglutamyl dipeptides, as well as lactoyl amino acids, were identified in the acidic fraction of soy sauce. They were chemically synthesized for confirmation of their occurrence and quantified in the selected reaction monitoring (SRM) mode. Pyroglutamyl dipeptides accounted for 770 mg/kg of soy sauce, followed by lactoyl amino acids (135 mg/kg) and γ-glutamyl dipeptides (70 mg/kg). In addition, N-succinoylglutamic acid was identified for the first time in food as a minor compound in soy sauce (5 mg/kg). Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Characterisation of the Redox Sensitive NMDA Receptor

KAUST Repository

Alzahrani, Ohood

2016-05-01

Glucose entry into the brain and its subsequent metabolism to L-lactate, regulated by astrocytes, plays a major role in synaptic plasticity and memory formation. A recent study has shown that L-lactate produced by the brain upon stimulation of glycolysis, and glycogen-derived L-lactate from astrocytes and its transport into neurons, is crucial for memory formation. A recent study revealed the molecular mechanisms that underlie the role of L-lactate in neuronal plasticity and long-term memory formation. L-lactate was shown to induce a cascade of molecular events via modulation of redox-sensitive N-Methyl-D-aspartate (NMDA) receptor activity that was mimicked by nicotinamide adenine dinucleotide hydride (NADH) co-enzyme. This indicated that changes in cellular redox state, following L-lactate transport inside the cells and its subsequent metabolism, production of NADH, and favouring a reduced state are the key effects of L-lactate. Therefore, we are investigating the role of L-lactate in modulating NMDA receptor function via redox modulatory sites. Accordingly, crucial redox-sensitive cysteine residues, Cys320 and Cys87, of the NR2A NMDA receptor subunit are mutated using site-directed mutation, transfected, and expressed in HEK293 cells. This cellular system will then be used to characterise and monitor its activity upon Llactate stimulation, compared to the wild type. This will be achieved by calcium imaging, using fluorescent microscopy. Our data shows that L-lactate potentiated NMDA receptor activity and increased intracellular calcium influx in NR1/NR2A wild type compared to the control condition (WT NR1/NR2A perfused with (1μM) glutamate and (1μM) glycine agonist only), showing faster response initiation and slower decay rate of the calcium signal to the baseline. Additionally, stimulating with L-lactate associated with greater numbers of cells having high fluorescent intensity (peak amplitude) compared to the control. Furthermore, L-lactate rescued the

Regulation of Arterial Pressure By The Paraventricular Nucleus in Conscious Rats: Interactions Among Glutamate, GABA, and Nitric Oxide

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Marli Cardoso Martins-Pinge

2013-01-01

Full Text Available The paraventricular nucleus (PVN of the hypothalamus is an important site for autonomic and neuroendocrine regulation. Experiments in anesthetized animals and in vitro indicate an interaction among gamma-aminobutyric acid (GABA, nitric oxide (NO and glutamate in the PVN. The cardiovascular role of the PVN and interactions of these neurotransmitters in conscious animals have not been evaluated fully. In chronically instrumented conscious rats, mean arterial pressure (MAP and heart rate (HR responses to microinjections (100 nl in the region of the PVN were tested. Bilateral blockade of ionotropic excitatory amino acid (EAA receptors (kynurenic acid, Kyn in the PVN produced small but significant decreases in MAP and HR. GABAA receptor blockade (bicuculline, Bic, and inhibition of NO synthase (N-(G-monomethyl-L-arginine, L-NMMA each increased MAP and HR. The NO donor sodium nitroprusside (SNP produced depressor responses that were attenuated by Bic. NO synthase inhibition potentiated both pressor responses to the selective EAA agonist, N-methyl-D-aspartic acid (NMDA, and depressor responses to Kyn. Increases in MAP and HR due to Bic were blunted by prior blockade of EAA receptors. Thus, pressor responses to GABA blockade require EAA receptors and GABA neurotransmission contributes to NO inhibition. Tonic excitatory effects of glutamate in the PVN are tonically attenuated by NO. These data demonstrate that, in the PVN of conscious rats, GABA, glutamate and NO interact in a complex fashion to regulate arterial pressure and heart rate under normal conditions.

Α-amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4.

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Lemonnier, Gérald; Lion, Cédric; Quirion, Jean-Charles; Pin, Jean-Philippe; Goudet, Cyril; Jubault, Philippe

2012-08-01

Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Studying specific effects of nootropic drugs on glutamate receptors in the rat brain].

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Firstova, Iu Iu; Vasil'eva, E V; Kovalev, G I

2011-01-01

The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.

Development and Validation of a HPTLC Method for Simultaneous Estimation of L-Glutamic Acid and γ-Aminobutyric Acid in Mice Brain.

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Sancheti, J S; Shaikh, M F; Khatwani, P F; Kulkarni, Savita R; Sathaye, Sadhana

2013-11-01

A new robust, simple and economic high performance thin layer chromatographic method was developed for simultaneous estimation of L-glutamic acid and γ-amino butyric acid in brain homogenate. The high performance thin layer chromatographic separation of these amino acid was achieved using n-butanol:glacial acetic acid:water (22:3:5 v/v/v) as mobile phase and ninhydrin as a derivatising agent. Quantitation of the method was achieved by densitometric method at 550 nm over the concentration range of 10-100 ng/spot. This method showed good separation of amino acids in the brain homogenate with Rf value of L-glutamic acid and γ-amino butyric acid as 21.67±0.58 and 33.67±0.58, respectively. The limit of detection and limit of quantification for L-glutamic acid was found to be 10 and 20 ng and for γ-amino butyric acid it was 4 and 10 ng, respectively. The method was also validated in terms of accuracy, precision and repeatability. The developed method was found to be precise and accurate with good reproducibility and shows promising applicability for studying pathological status of disease and therapeutic significance of drug treatment.

Synthesis of new isoxazoline-based acidic amino acids and investigation of their affinity and selectivity profile at ionotropic glutamate receptors

DEFF Research Database (Denmark)

Pinto, Andrea; Conti, Paola; Grazioso, Giovanni

2011-01-01

The synthesis of four new isoxazoline-based amino acids being analogues of previously described glutamate receptor ligands is reported and their affinity for ionotropic glutamate receptors is analyzed in comparison with that of selected model compounds. Molecular modelling investigations have been...

The role of neonatal NMDA receptor activation in defeminization and masculinization of sex behavior in the rat

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Schwarz, Jaclyn M.; McCarthy, Margaret M.

2008-01-01

Normal development of the male rat brain involves two distinct processes, masculinization and defeminization, that occur during a critical period of brain sexual differentiation. Masculinization allows for the capacity to express male sex behavior in adulthood, and defeminization eliminates or suppresses the capacity to express female sex behavior in adulthood. Despite being separate processes, both masculinization and defeminization are induced by neonatal estradiol exposure. Though the mechanisms underlying estradiol-mediated masculinization of behavior during development have been identified, the mechanisms underlying defeminization are still unknown. We sought to determine whether neonatal activation of glutamate NMDA receptors is a necessary component of estradiol-induced defeminization of behavior. We report here that antagonizing glutamate receptors during the critical period of sexual differentiation blocks estradiol-induced defeminization but not masculinization of behavior in adulthood. However, enhancing NMDA receptor activation during the same critical period mimics estradiol to permanently induce both defeminization and masculinization of sexual behavior. PMID:18687334

Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively

DEFF Research Database (Denmark)

Collins, C; Duff, C; Duncan, A M

1993-01-01

to human chromosome 8 using a somatic cell hybrid panel. Because the gene causing HD has been localized to chromosome 4p16.3, the chromosome assignments reported here are inconsistent with either of these genes playing a causative role in the molecular pathology of HD. However, it is noteworthy......A role for the N-methyl-D-aspartate (NMDA) receptor in the molecular pathology underlying Huntington disease (HD) has been proposed on the basis of neurochemical studies in HD and the ability of the NMDA receptor to mediate neuronal cell death. The molecular cloning of the human NMDA receptor...

Rich biotin content in lignocellulose biomass plays the key role in determining cellulosic glutamic acid accumulation by Corynebacterium glutamicum.

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Wen, Jingbai; Xiao, Yanqiu; Liu, Ting; Gao, Qiuqiang; Bao, Jie

2018-01-01

Lignocellulose is one of the most promising alternative feedstocks for glutamic acid production as commodity building block chemical, but the efforts by the dominant industrial fermentation strain Corynebacterium glutamicum failed for accumulating glutamic acid using lignocellulose feedstock. We identified the existence of surprisingly high biotin concentration in corn stover hydrolysate as the determining factor for the failure of glutamic acid accumulation by Corynebacterium glutamicum . Under excessive biotin content, induction by penicillin resulted in 41.7 ± 0.1 g/L of glutamic acid with the yield of 0.50 g glutamic acid/g glucose. Our further investigation revealed that corn stover contained 353 ± 16 μg of biotin per kg dry solids, approximately one order of magnitude greater than the biotin in corn grain. Most of the biotin remained stable during the biorefining chain and the rich biotin content in corn stover hydrolysate almost completely blocked the glutamic acid accumulation. This rich biotin existence was found to be a common phenomenon in the wide range of lignocellulose biomass and this may be the key reason why the previous studies failed in cellulosic glutamic acid fermentation from lignocellulose biomass. The extended recording of the complete members of all eight vitamin B compounds in lignocellulose biomass further reveals that the major vitamin B members were also under the high concentration levels even after harsh pretreatment. The high content of biotin in wide range of lignocellulose biomass feedstocks and the corresponding hydrolysates was discovered and it was found to be the key factor in determining the cellulosic glutamic acid accumulation. The highly reserved biotin and the high content of their other vitamin B compounds in biorefining process might act as the potential nutrients to biorefining fermentations. This study creates a new insight that lignocellulose biorefining not only generates inhibitors, but also keeps nutrients

Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification

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Christian Madry

2010-03-01

Full Text Available Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named excitatory glycine receptors. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I-V dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I-V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I-V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors.

Effect of l-glutamic acid supplementation on performance and nitrogen balance of broilers fed low protein diets.

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Bezerra, R M; Costa, F G P; Givisiez, P E N; Freitas, E R; Goulart, C C; Santos, R A; Souza, J G; Brandão, P A; Lima, M R; Melo, M L; Rodrigues, V P; Nogueira, E T; Vieira, D V G

2016-06-01

The aim of this study was to evaluate the effect of protein reduction and supplementation of l-glutamic acid in male broiler diets. A total of 648 chicks of the Cobb 500 strain were distributed in a completely randomized design with six treatments and six replications with eighteen birds per experimental unit. The study comprised pre-starter (1-7 days), starter (8-21 days), growth (22-35 days) and final (36-45 days) phases. The first treatment consisted of a control diet formulated according to the requirements of essential amino acids for each rearing phase. The second and third treatments had crude protein (CP) reduced by 1.8 and 3.6 percentage points (pp) in relation to the control diet respectively. In the fourth treatment, l-glutamic acid was added to provide the same glutamate level as the control diet, and in the last two treatments, the broilers were supplemented with 1 and 2 pp of glutamate above that of the control diet respectively. The reduction in CP decreased the performance of broilers and the supplementation of l-glutamic acid did not influence performance when supplied in the diets with excess of glutamate. The lowest excreted nitrogen values were observed in the control diet, and treatments 2 and 3, respectively, in comparison with treatments with the use of l-glutamic acid (5 and 6). Retention efficiency of nitrogen was better in the control diet and in the treatment with a reduction of 1.8 pp of CP. It was verified that the serum uric acid level decreased with the CP reduction. A reduction in CP levels of up to 21.3%, 18.8%, 18.32% and 17.57% is recommended in phases from 1 to 7, 8 to 21, 22 to 35 and at 36 to 42 days, respectively, with a level of glutamate at 5.32%, 4.73%, 4.57%, 4.38%, also in these phases. Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.

Enhanced Production of Poly-γ-glutamic Acid by Bacillus licheniformis TISTR 1010 with Environmental Controls.

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Kongklom, Nuttawut; Shi, Zhongping; Chisti, Yusuf; Sirisansaneeyakul, Sarote

2017-07-01

Bacillus licheniformis TISTR 1010 was used for glutamic acid-independent production of poly-γ-glutamic acid (γ-PGA). A fed-batch production strategy was developed involving feedings of glucose, citric acid, and ammonium chloride at specified stages of the fermentation. With the dissolved oxygen concentration controlled at ≥50% of air saturation and the pH controlled at ~7.4, the fed-batch operation at 37 °C afforded a peak γ-PGA concentration of 39.9 ± 0.3 g L -1 with a productivity of 0.926 ± 0.006 g L -1  h -1 . The observed productivity was nearly threefold greater than previously reported for glutamic acid-independent production using the strain TISTR 1010. The molecular weight of γ-PGA was in the approximate range of 60 to 135 kDa.

Amino acid transamination is crucial for ischaemic cardioprotection in normal and preconditioned isolated rat hearts--focus on L-glutamate

DEFF Research Database (Denmark)

Løfgren, Bo; Povlsen, Jonas Agerlund; Rasmussen, Lars Ege

2010-01-01

We have found that cardioprotection by l-glutamate mimics protection by classical ischaemic preconditioning (IPC). We investigated whether the effect of IPC involves amino acid transamination and whether IPC modulates myocardial glutamate metabolism. In a glucose-perfused, isolated rat heart model...... subjected to 40 min global no-flow ischaemia and 120 min reperfusion, the effects of IPC (2 cycles of 5 min ischaemia and 5 min reperfusion) and continuous glutamate (20 mm) administration during reperfusion on infarct size and haemodynamic recovery were studied. The effect of inhibiting amino acid...... transamination was evaluated by adding the amino acid transaminase inhibitor amino-oxyacetate (AOA; 0.025 mm) during reperfusion. Changes in coronary effluent, interstitial (microdialysis) and intracellular glutamate ([GLUT](i)) concentrations were measured. Ischaemic preconditioning and postischaemic glutamate...

Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent.

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Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus

2014-01-01

Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.

Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: Implications for its efficacy in bipolar disorder

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Ramadan, Epolia; Basselin, Mireille; Rao, Jagadeesh S.; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I.

2011-01-01

An upregulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-D-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release arachidonic acid (AA) from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signaling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanesthetized rats that had been treated p.o. daily for 42 days with vehicle or a therapeutically relevant dose of LTG (10 mg/kg/.d). Regional brain AA incorporation coefficients k* and rates Jin, AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and Jin in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signaling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signaling are up-regulated in the postmortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade. PMID:21733229

Long-term potentiation in the CA1 hippocampus induced by NR2A subunit-containing NMDA glutamate receptors is mediated by Ras-GRF2/Erk map kinase signaling.

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Shan-xue Jin

Full Text Available BACKGROUND: NMDA-type glutamate receptors (NMDARs are major contributors to long-term potentiation (LTP, a form of synaptic plasticity implicated in the process of learning and memory. These receptors consist of calcium-permeating NR1 and multiple regulatory NR2 subunits. A majority of studies show that both NR2A and NR2B-containing NMDARs can contribute to LTP, but their unique contributions to this form of synaptic plasticity remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that NR2A and NR2B-containing receptors promote LTP differently in the CA1 hippocampus of 1-month old mice, with the NR2A receptors functioning through Ras-GRF2 and its downstream effector, Erk Map kinase, and NR2B receptors functioning independently of these signaling molecules. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that NR2A-, but not NR2B, containing NMDA receptors induce LTP in pyramidal neurons of the CA1 hippocampus from 1 month old mice through Ras-GRF2 and Erk. This difference add new significance to the observation that the relative levels of these NMDAR subtypes is regulated in neurons, such that NR2A-containing receptors become more prominent late in postnatal development, after sensory experience and synaptic activity.

Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia

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Colin Kehrer

2008-04-01

Full Text Available Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDAreceptor subtype in the etiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

Cholesterol modulates open probability and desensitization of NMDA receptors

Czech Academy of Sciences Publication Activity Database

Kořínek, Miloslav; Vyklický, Vojtěch; Borovská, Jiřina; Lichnerová, Katarina; Kaniaková, Martina; Krausová, Barbora; Krůšek, Jan; Balík, Aleš; Smejkalová, Tereza; Horák, Martin; Vyklický ml., Ladislav

2015-01-01

Roč. 593, č. 10 (2015), s. 2279-2293 ISSN 0022-3751 R&D Projects: GA ČR(CZ) GPP303/11/P391; GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA14-02219S; GA ČR(CZ) GP14-09220P; GA TA ČR(CZ) TE01020028; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : NMDA receptor * glutamate-gated * cholesterol Subject RIV: ED - Physiology Impact factor: 4.731, year: 2015

Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors

DEFF Research Database (Denmark)

Conti, Paola; Grazioso, Giovanni; di Ventimiglia, Samuele Joppolo

2005-01-01

N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors...

Lipoic acid effects on glutamate and taurine concentrations in rat hippocampus after pilocarpine-induced seizures

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P S Santos

2011-01-01

Full Text Available Pilocarpine-induced seizures can be mediated by increases in oxidative stress and by cerebral amino acid changes. The present research suggests that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures in cellular level. The objective of the present study was to evaluate the lipoic acid (LA effects in glutamate and taurine contents in rat hippocampus after pilocarpine-induced seizures. Wistar rats were treated intraperitoneally (i.p. with 0.9% saline (Control, pilocarpine (400 mg/kg, Pilocarpine, LA (10 mg/kg, LA, and the association of LA (10 mg/kg plus pilocarpine (400 mg/kg, that was injected 30 min before of administration of LA (LA plus pilocarpine. Animals were observed during 24 h. The amino acid concentrations were measured using high-performance liquid chromatograph (HPLC. In pilocarpine group, it was observed a significant increase in glutamate content (37% and a decrease in taurine level (18% in rat hippocampus, when compared to control group. Antioxidant pretreatment significantly reduced the glutamate level (28% and augmented taurine content (32% in rat hippocampus, when compared to pilocarpine group. Our findings strongly support amino acid changes in hippocampus during seizures induced by pilocarpine, and suggest that glutamate-induced brain damage plays a crucial role in pathogenic consequences of seizures, and imply that strong protective effect could be achieved using lipoic acid through the release or decrease in metabolization rate of taurine amino acid during seizures.

LOCALIZATION OF NMDA AND AMPA RECEPTORS IN RAT BARREL FIELD

NARCIS (Netherlands)

JAARSMA, D; SEBENS, JB; KORF, J

1991-01-01

The aim of this study was to asses the distribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) receptors in the barrel field of rat primary somatosensory (SI) cortex using light-microscopic in vitro autoradiography. NMDA receptors were labeled

Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of Unilateral 6-hydroxydopamine induced Parkinson's rats: Effect of 5-HT, GABA and bone marrow cell supplementation

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Romeo Chinthu

2011-01-01

Full Text Available Abstract Parkinson's disease is characterized by progressive cell death in the substantia nigra pars compacta, which leads to dopamine depletion in the striatum and indirectly to cortical dysfunction. Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease and glutamate receptor mediated excitotoxicity has been suggested to be one of the possible causes of the neuronal degeneration. In the present study, the effects of serotonin, gamma-aminobutyric acid and bone marrow cells infused intranigrally to substantia nigra individually and in combination on unilateral 6-hydroxydopamine induced Parkinson's rat model was analyzed. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in Bmax (P

Selective fluorescent detection of aspartic acid and glutamic acid employing dansyl hydrazine dextran conjugate.

Science.gov (United States)

Nasomphan, Weerachai; Tangboriboonrat, Pramuan; Tanapongpipat, Sutipa; Smanmoo, Srung

2014-01-01

Highly water soluble polymer (DD) was prepared and evaluated for its fluorescence response towards various amino acids. The polymer consists of dansyl hydrazine unit conjugated into dextran template. The conjugation enhances higher water solubility of dansyl hydrazine moiety. Of screened amino acids, DD exhibited selective fluorescence quenching in the presence of aspartic acid (Asp) and glutamic acid (Glu). A plot of fluorescence intensity change of DD against the concentration of corresponding amino acids gave a good linear relationship in the range of 1 × 10(-4) M to 25 × 10(-3) M. This establishes DD as a potential polymeric sensor for selective sensing of Asp and Glu.

Fermentation and recovery of L-glutamic acid from cassava starch hydrolysate by ion-exchange resin column

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Nampoothiri K. Madhavan

1999-01-01

Full Text Available Investigations were carried out with the aim of producing L-glutamic acid from Brevibacterium sp. by utilizing a locally available starchy substrate, cassava (Manihot esculenta Crantz. Initial studies were carried out in shake flasks, which showed that even though the yield was high with 85-90 DE (Dextrose Equivalent value, the maximum conversion yield (~34% was obtained by using only partially digested starch hydrolysate, i.e. 45-50 DE. Fermentations were carried out in batch mode in a 5 L fermenter, using suitably diluted cassava starch hydrolysate, using a 85-90 DE value hydrolysate. Media supplemented with nutrients resulted in an accumulation of 21 g/L glutamic acid with a fairly high (66.3% conversation yield of glucose to glutamic acid (based on glucose consumed and on 81.74% theoretical conversion rate. The bioreactor conditions most conducive for maximum production were pH 7.5, temperature 30°C and an agitation of 180 rpm. When fermentation was conducted in fed-batch mode by keeping the residual reducing sugar concentration at 5% w/v, 25.0 g/L of glutamate was obtained after 40 h fermentation (16% more the batch mode. Chromatographic separation by ion-exchange resin was used for the recovery and purification of glutamic acid. It was further crystallized and separated by making use of its low solubility at the isoelectric point (pH 3.2.

The dissolution of natural and artificial dusts in glutamic acid

Science.gov (United States)

Ling, Zhang; Faqin, Dong; Xiaochun, He

2015-06-01

This article describes the characteristics of natural dusts, industrial dusts, and artificial dusts, such as mineral phases, chemical components, morphological observation and size. Quartz and calcite are the main phases of natural dusts and industrial dusts with high SiO2 and CaO and low K2O and Na2O in the chemical composition. The dissolution and electrochemical action of dusts in glutamic acid liquor at the simulated human body temperature (37 °C) in 32 h was investigated. The potential harm that the dust could lead to in body glutamic acid acidic environment, namely biological activity, is of great importance for revealing the human toxicological mechanism. The changes of pH values and electric conductivity of suspension of those dusts were similar, increased slowly in the first 8 h, and then the pH values increased rapidly. The total amount of dissolved ions of K, Ca, Na, and Mg was 35.4 to 429 mg/kg, particularly Ca was maximal of 20 to 334 mg/kg. The total amount of dissolved ions of Fe, Zn, Mn, Pb, and Ba was 0.18 to 5.59 mg/kg and in Al and Si was 3.0 to 21.7 mg/kg. The relative solubility order of dusts in glutamic acid is wollastonite > serpentine > sepiolite, the cement plant industrial dusts > natural dusts > power plant industrial dusts. The wollastonite and cement plant industrial dusts have the highest solubility, which also have high content of CaO; this shows that there are a poorer corrosion-resisting ability and lower bio-resistibility. Sepiolite and power plant industrial dusts have lowest solubility, which also have high content of SiO2; this shows that there are a higher corrosion-resisting ability and stronger bio-resistibility.

Gas-phase salt bridge interactions between glutamic acid and arginine

NARCIS (Netherlands)

Jaeqx, S.; Oomens, J.; Rijs, A.M.

2013-01-01

The gas-phase side chain-side chain (SC-SC) interaction and possible proton transfer between glutamic acid (Glu) and arginine (Arg) residues are studied under low-temperature conditions in an overall neutral peptide. Conformation-specific IR spectra, obtained with the free electron laser FELIX, in

Vitamin E-Mediated Modulation of Glutamate Receptor Expression in an Oxidative Stress Model of Neural Cells Derived from Embryonic Stem Cell Cultures

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Afifah Abd Jalil

2017-01-01

Full Text Available Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate in the brain can be excitotoxic and cause oxidative stress, which is associated with Alzheimer’s disease. In the present study, the effects of vitamin E in the form of tocotrienol-rich fraction (TRF and alpha-tocopherol (α-TCP in modulating the glutamate receptor and neuron injury markers in an in vitro model of oxidative stress in neural-derived embryonic stem (ES cell cultures were elucidated. A transgenic mouse ES cell line (46C was differentiated into a neural lineage in vitro via induction with retinoic acid. These cells were then subjected to oxidative stress with a significantly high concentration of glutamate. Measurement of reactive oxygen species (ROS was performed after inducing glutamate excitotoxicity, and recovery from this toxicity in response to vitamin E was determined. The gene expression levels of glutamate receptors and neuron-specific enolase were elucidated using real-time PCR. The results reveal that neural cells derived from 46C cells and subjected to oxidative stress exhibit downregulation of NMDA, kainate receptor, and NSE after posttreatment with different concentrations of TRF and α-TCP, a sign of neurorecovery. Treatment of either TRF or α-TCP reduced the levels of ROS in neural cells subjected to glutamate-induced oxidative stress; these results indicated that vitamin E is a potent antioxidant.

Catalysis of the Oligomerization of O-Phospho-Serine, Aspartic Acid, or Glutamic Acid by Cationic Micelles

Science.gov (United States)

Bohler, Christof; Hill, Aubrey R., Jr.; Orgel, Leslie E.

1996-01-01

Treatment of relatively concentrated aqueous solutions of 0-phospho-serine (50 mM), aspartic acid (100 mM) or glutamic acid (100 mM) with carbonyldiimidazole leads to the formation of an activated intermediate that oligomerizes efficiently. When the concentration of amino acid is reduced tenfold, few long oligomers can be detected. Positively-charged cetyltrimethyl ammonium bromide micelles concentrate the negatively-charged activated intermediates of the amino acids at their surfaces and catalyze efficient oligomerization even from dilute solutions.

Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology

DEFF Research Database (Denmark)

Stensbøl, Tine B; Uhlmann, Peter; Morel, Sandrine

2002-01-01

A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including ...

Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures

DEFF Research Database (Denmark)

Kristensen, Bjarne Winther; Noraberg, J; Zimmer, J

2001-01-01

) values was found after 2 days of exposure: AMPA (3.7 mM)>NMDA (11 mM)=KA (13 mM)>ATPA (33 mM). Exposed to 30 microM ATPA, 3 microM AMPA and 10 microM NMDA, CA1 was the most susceptible subfield followed by fascia dentata and CA3. Using 8 microM KA, CA3 was the most susceptible subfield, followed...... by fascia dentata and CA1. In 100 microM concentrations, all four agonists induced the same, maximal PI uptake in all hippocampal subfields, corresponding to total neuronal degeneration. Using glutamate receptor antagonists, like GYKI 52466, NBQX and MK-801, inhibition data revealed that AMPA excitotoxicity...

Changes in Glutamate/NMDA Receptor Subunit 1 Expression in Rat Brain after Acute and Subacute Exposure to Methamphetamine

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Walailuk Kerdsan

2009-01-01

Full Text Available Methamphetamine (METH is a psychostimulant drug of abuse that produces long-term behavioral changes including behavioral sensitization, tolerance, and dependence. METH has been reported to induce neurotoxic effects in several areas of the brain via the dopaminergic system. Changes of dopamine function can induce malfunction of the glutamatergic system. Therefore, the aim of the present study was to examine the effects of METH administration on the expression of glutamate N-methyl-D-aspartate receptor subunit 1 (NMDAR1 in frontal cortex, striatum, and hippocampal formation after acute and subacute exposure to METH by western blotting. Male Sprague-Dawley rats were injected intraperitoneally with a single dose of 8 mg/kg METH, 4 mg/kg/day METH for 14 days and saline in acute, subacute, and control groups, respectively. A significant increase in NMDAR1 immunoreactive protein was found in frontal cortex in the subacute group (P=.036 but not in the acute group (P=.580. Moreover, a significant increase in NMDAR1 was also observed in striatum in both acute (P=.025 and subacute groups (P=.023. However, no significant differences in NMDAR1 in hippocampal formation were observed in either acute or subacute group. The results suggest that an upregulation of NMDA receptor expression may be a consequence of glutamatergic dysfunction induced by METH.

Pharmacology of (S)-homoquisqualic acid and (S)-2-amino-5-phosphonopentanoic acid [(S)-AP5] at cloned metabotropic glutamate receptors

DEFF Research Database (Denmark)

Bräuner-Osborne, Hans; Krogsgaard-Larsen, P

1998-01-01

1 In this study we have determined the pharmacological profile of (S)-quisqualic acid, (S)-2-amino-4-phosphonobutyric acid ((S)-AP4) and their higher homologues (S)-homoquisqualic acid, (S)-2-amino-5-phosphonopentanoic acid ((S)-AP5), respectively, and (R)-AP5 at subtypes of metabotropic (S)-glutamic...... demonstrate that incorporation of an additional carbon atom into the backbone of (S)-glutamic acid and its analogues, to give the corresponding homologues, and replacement of the terminal carboxyl groups by isosteric acidic groups have profound effects on the pharmacological profiles at mGlu receptor subtypes...... acid (mGlu) receptors expressed in Chinese hamster ovary cells. 2 (S)-Quisqualic acid was a potent mGlu1/mGlu5 agonist (EC50 values of 1.1 microM and 0.055 microM, respectively) showing no activity at mGlu2 and weak agonism at mGlu4 (EC50 approximately 1000 microM). 3 (S)-Homoquisqualic acid displayed...

AUTOANTIBODIES TO GLUTAMIC ACID DECARBOXYLASE AS A PATHOGENETIC MARKER OF TYPE I DIABETES MELLITUS

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N. V. Piven

2011-01-01

Full Text Available Abstract. A new method of enzyme-linked immunosorbent assay (in solid-phase ELISA format has been developed to determine concentrations of autoantibodies to glutamic acid decarboxylase, as well as an evidencebased methodology is proposed for its medical implications, as a quantitative pathogenetic predictive marker of autoimmune diagnostics in type 1 diabetes mellitus. This technique could be implied for serial production of diagnostic reagent kits, aimed for detection of autoantibodies to glutamic acid decarboxylase by means of ELISA approach. (Med. Immunol., 2011, vol. 13, N 2-3, pp 257-260

Computational study of NMDA conductance and cortical oscillations in schizophrenia

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Kubra eKomek Kirli

2014-10-01

Full Text Available N-methyl-D-aspartate (NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia. The illness is also characterized by gamma oscillatory disturbances, which can be evaluated with precise frequency specificity employing auditory cortical entrainment paradigms. This computational study investigates how synaptic NMDA hypofunction may give rise to network level oscillatory deficits as indexed by entrainment paradigms. We developed a computational model of a local cortical circuit with pyramidal cells and fast-spiking interneurons (FSI, incorporating NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA, and γ-aminobutyric acid (GABA synaptic kinetics. We evaluated the effects of varying NMDA conductance on FSIs and pyramidal cells, as well as AMPA to NMDA ratio. We also examined the differential effects across a broad range of entrainment frequencies as a function of NMDA conductance. Varying NMDA conductance onto FSIs revealed an inverted-U relation with network gamma whereas NMDA conductance onto the pyramidal cells had a more monotonic relationship. Varying NMDA vs. AMPA conductance onto FSIs demonstrated the necessity of AMPA in the generation of gamma while NMDA receptors had a modulatory role. Finally, reducing NMDA conductance onto FSI and varying the stimulus input frequency reproduced the specific reductions in gamma range (~40 Hz as observed in schizophrenia studies. Our computational study showed that reductions in NMDA conductance onto FSIs can reproduce similar disturbances in entrainment to periodic stimuli within the gamma range as reported in schizophrenia studies. These findings provide a mechanistic account of how specific cellular level disturbances can give rise to circuitry level pathophysiologic disturbance in schizophrenia.

Detection of Glutamate and γ-aminobutyric Acid in Vitreous of Patients with Proliferative Diabetic Retinopathy

Institute of Scientific and Technical Information of China (English)

Juan Deng; De-Zheng Wu; Rulong Gao

2000-01-01

Purpose: To study the levels of glutamate and γ-aminobutyric acid (GABA) in vitreous of patients with proliferative diabetic retinopathy(PDR) and to investigate their roles in retinal ischemia.Method: Vitreous samples were collected from 25 patients (27 eyes) with PDR and 14patients ( 14 eyes) with idiopathic macular hole. Glutamate and GABA detection were performed by high-performance liquid chromatography (HPLC).Results: Patients with PDR had significantly higher concentrations of glutamate and GABA than the control group. The glutamate level has a significantly positive correlation with GABA level.Conclusion: Detection of glutamate and GABA in vitreous provides biochemical support for the mechanism and treatment of ischemic retinal damage in patients with PDR.

Production of L-glutamic Acid with Corynebacterium glutamicum (NCIM 2168) and Pseudomonas reptilivora (NCIM 2598): A Study on Immobilization and Reusability.

Science.gov (United States)

Shyamkumar, Rajaram; Moorthy, Innasi Muthu Ganesh; Ponmurugan, Karuppiah; Baskar, Rajoo

2014-07-01

L-glutamic acid is one of the major amino acids that is present in a wide variety of foods. It is mainly used as a food additive and flavor enhancer in the form of sodium salt. Corynebacterium glutamicum (C. glutamicum) is one of the major organisms widely used for glutamic acid production. The study was dealing with immobilization of C. glutamicum and mixed culture of C. glutamicum and Pseudomonas reptilivora (P. reptilivora) for L-glutamic acid production using submerged fermentation. 2, 3 and 5% sodium alginate concentrations were used for production and reusability of immobilized cells for 5 more trials. The results revealed that 2% sodium alginate concentration produced the highest yield (13.026±0.247 g/l by C. glutamicum and 16.026±0.475 g/l by mixed immobilized culture). Moreover, reusability of immobilized cells was evaluated in 2% concentration with 5 more trials. However, when the number of cycles increased, the production of L-glutamic acid decreased. Production of glutamic acid using optimized medium minimizes the time needed for designing the medium composition. It also minimizes external contamination. Glutamic acid production gradually decreased due to multiple uses of beads and consequently it reduces the shelf life.

Protective effects of dietary glycine and glutamic acid toward the toxic effects of oxidized mustard oil in rabbits.

Science.gov (United States)

Zeb, Alam; Rahman, Saleem Ur

2017-01-25

The protective role of glycine and glutamic acid against the toxic effects of oxidized oil was studied for the first time. Mustard seed oil was thermally oxidized and characterized for quality characteristics and polyphenolic composition using reversed phase HPLC-DAD. Significant changes in the quality characteristics occurred with thermal oxidation. Fourteen polyphenolic compounds were identified and quantified in oils. Quercetin-3-glucoside, quercetin-3-feruloylsophoroside, catechin, quercetin-3-rutinoside, quercetin-3,7-diglucoside, sinapic acid and vanillic acid hexoside were the major compounds in the fresh and oxidized oil. Oxidized, un-oxidized mustard oils, glycine and glutamic acid were given to rabbits alone or in combination. The biochemical responses were studied in terms of haematological and biochemical parameters and histopathology. It has been observed that biochemical and haematological parameters were adversely affected by the oxidized oil, while supplementation of both amino acids was beneficial in normalizing these parameters. Both amino acids alone have no significant effects, however, oxidized oil affected the liver by enhancing fat accumulation, causing hepatitis, reactive Kupffer cells and necrosis. The co-administration of oxidized oils with glycine or glutamic acid revealed significant recovery of the liver structure and function. In conclusion, glycine or glutamic acid is beneficial and protective against food toxicity and can be considered as an ameliorative food supplement.

Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

International Nuclear Information System (INIS)

Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko; Yamasaki, Yoshiko; Matsuda, Sachi; Okamoto, Yukari; Sekimoto, Teruki; Fukatsu, Anna; Nishikawa, Hiroyuki; Kume, Toshiaki; Fukushima, Nobuyuki; Akaike, Akinori; Kawabata, Atsufumi

2011-01-01

Highlights: ► Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. ► Activation of ERK mediates the toxicity of hydrogen sulfide. ► Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H 2 S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H 2 S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H 2 S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.

Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor Responses

Science.gov (United States)

Paganelli, Meaghan A.

2015-01-01

NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain. In addition to blocking Na+ channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed current decrease to two main mechanisms: a voltage-dependent “foot-in-the-door” pore block and an allosteric gating effect. Further, the inhibition was state-independent because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic approaches in chronic pain. PMID:25589775

L-Glutamic acid production by Bacillus spp. isolated from vegetable ...

African Journals Online (AJOL)

Administrator

2011-06-15

Jun 15, 2011 ... 2Department of Botany and Microbiology, University of Ibadan, Ibadan, Oyo state, Nigeria. ... monosodium salt as a flavor enhancer in foods (Kikunae, ...... Madhavan KN, Ashok P (1996). Solid state fermentation for L – glutamic acid production using Brevibacterium sp. DSM 20411. J. Food. Sci. Technol.

Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

Science.gov (United States)

Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2012-01-01

N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

Characterization of depolarization-coupled release of glutamate from cultured mouse cerebellar granule cells using DL-threo-beta-benzyloxyaspartate (DL-TBOA) to distinguish between the vesicular and cytoplasmic pools

DEFF Research Database (Denmark)

Bak, Lasse K; Schousboe, Arne; Waagepetersen, Helle S

2003-01-01

Release of preloaded [3H]D-aspartate in response to depolarization induced by N-methyl-D-aspartate (NMDA) or the endogenous agonist glutamate was characterized using cultured glutamatergic cerebellar granule neurons. Release from the vesicular and the cytoplasmic glutamate pools, respectively, wa...

Conantokin probes of NMDA receptors in normal and Alzheimer disease human cerebral cortex

International Nuclear Information System (INIS)

Ragnarsson, L.; Dodd, P.R.; Lewis, R.J.

2002-01-01

Full text: The pharmacology of the N-methyl-D-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer disease cases and matched controls. The affinity and density of the [ 3 H]MK-801 binding site were delineated along with the enhancement of [ 3 H]MK-801 binding by glutamate and spermine. Sites with distinct pharmacologies were distributed regionally through the cortex. The differences could not be explained by variations in the parameters of [ 3 H]MK-801 binding; rather, the data suggest that the subunit composition of NMDA receptors may be locally variable. Selective differences were also found between controls and Alzheimer disease cases in certain brain regions. The interactions of human NMDA sites with the Ala(7) and Lys(7) derivatives of conantokin-G (Con-G) were also characterized. Ala(7)-con-G showed the higher affinity of the two peptides, and also defined two distinct binding sites in controls. In distinction to the Ala(7) peptide, Lys(7)- con-G showed preferential binding to receptor sites in Alzheimer disease cf. control brain. Modified conantokins are useful for identifying differences in subunit composition of the NMDA receptors between brain areas. They may also have potential as protective agents against over-excitation mediated by specific NMDA receptors, which might contribute to localized brain damage in Alzheimer disease. For further characterization of the pharmacology of different NMDA receptor subunits, a mammalian expression system has been developed for the analysis of their responses to selected ligands, including conantokins. Copyright (2002) Australian Neuroscience Society

Lysine and Glutamic Acids as the End Products of Multi-response of Optimized Fermented Medium by Mucor mucedo KP736529.

Science.gov (United States)

El-Hersh, Mohammed S; Saber, WesamEldin I A; El-Fadaly, Husain A; Mahmoud, Mohammed K

Amino acids are important for living organisms, they acting as crucial for metabolic activities and energy generation, wherein the deficiency in these amino acids cause various physiological defects. The aim of this study is to investigate the effect of some nutritional factors on the amino acids production by Mucor mucedo KP736529 during fermentation intervals. Mucor mucedo KP736529 was selected according to proteolytic activity. Corn steep liquor and olive cake were used in the fermented medium during Placket-Burman and central composite design to maximize the production of lysine and glutamic acids. During the screening by Plackett-Burman design, olive cake and Corn Steep Liquor (CSL) had potential importance for the higher production of amino acids. The individual fractionation of total amino acids showed both lysine and glutamic as the major amino acids associated with the fermentation process. Moreover, the Central Composite Design (CCD) has been adopted to explain the interaction between olive cake and CSL on the production of lysine and glutamic acids. The model recorded significant F-value, with high values of R 2, adjusted R 2 and predicted R 2 for both lysine and glutamic, indicating the validity of the data. Solving equation for maximum production of lysine recorded theoretical levels of olive cake and CSL, being 2.58 and 1.83 g L -1, respectively, with predicting value of lysine at 1.470 μg mL -1, whereas the predicting value of glutamic acid reached 0.805 mg mL -1 at levels of 2.49 and 1.93 g L -1 from olive cake and CSL, respectively. The desirability function (D) showed the actual responses being 1.473±0.009 and 0.801±0.004 μg mL -1 for lysine and glutamic acids, respectively. The model showed adequate validity to be applied in a large-scale production of both lysine and glutamic acids.

The metabotropic glutamate receptor agonist 1S,3R-ACPD stimulates and modulates NMDA receptor mediated excitotoxicity in organotypic hippocampal slice cultures

DEFF Research Database (Denmark)

Blaabjerg, M; Kristensen, Bjarne Winther; Bonde, C

2001-01-01

the PI uptake in both CA1 and CA3, compared to cultures exposed to 10 microM NMDA only. Adding the 300 microM ACPD as pretreatment for 30 min followed by a 30 min wash in normal medium before the ACPD/NMDA co-exposure, eliminated the potentiation of NMDA toxicity. The potentiation was also blocked...

Deletion of genes involved in glutamate metabolism to improve poly-gamma-glutamic acid production in B. amyloliquefaciens LL3.

Science.gov (United States)

Zhang, Wei; He, Yulian; Gao, Weixia; Feng, Jun; Cao, Mingfeng; Yang, Chao; Song, Cunjiang; Wang, Shufang

2015-02-01

Here, we attempted to elevate poly-gamma-glutamic acid (γ-PGA) production by modifying genes involved in glutamate metabolism in Bacillus amyloliquefaciens LL3. Products of rocR, rocG and gudB facilitate the conversion from glutamate to 2-oxoglutarate in Bacillus subtillis. The gene odhA is responsible for the synthesis of a component of the 2-oxoglutarate dehydrogenase complex that catalyzes the oxidative decarboxylation of 2-oxoglutarate to succinyl coenzyme A. In-frame deletions of these four genes were performed. In shake flask experiments the gudB/rocG double mutant presented enhanced production of γ-PGA, a 38 % increase compared with wild type. When fermented in a 5-L fermenter with pH control, the γ-PGA yield of the rocR mutant was increased to 5.83 g/L from 4.55 g/L for shake flask experiments. The gudB/rocG double mutant produced 5.68 g/L γ-PGA compared with that of 4.03 g/L for the wild type, a 40 % increase. Those results indicated the possibility of improving γ-PGA production by modifying glutamate metabolism, and identified potential genetic targets to improve γ-PGA production.

Central transport and distribution of labelled glutamic and aspartic acids to the cochlear nucleus in cats

International Nuclear Information System (INIS)

Kane, E.S.

1979-01-01

Tritiated L-glutamic acid or L-aspartic acid was injected unilaterally into the cochleas of adult cats, and 4 h-7 days later the localization of label was studied by light-microscopic autoradiography in sections of the brain stem. Consistent differences in labelling after glutamate and after aspartate suggest differences in their uptake, metabolic conversion and/or transport to the cochlear nucleus by cochlear fibers. The morphological differences shown here agree with the distribution of those two amino acids in the cat cochlear nucleus as shown by microchemical analyses. (author)

Relationship between glutamate dysfunction and symptoms and cognitive function in psychosis

Directory of Open Access Journals (Sweden)

Kate eMerritt

2013-11-01

Full Text Available The glutamate hypothesis of schizophrenia, proposed over two decades ago, originated following the observation that administration of drugs that block NMDA glutamate receptors, such as ketamine, could induce schizophrenia–like symptoms. Since then, this hypothesis has been extended to describe how glutamate abnormalities may disturb brain function and underpin psychotic symptoms and cognitive impairments. The glutamatergic system is now a major focus for the development of new compounds in schizophrenia. Relationships between regional brain glutamate function and symptom severity can be investigated using proton magnetic resonance spectroscopy (1H-MRS to estimate levels of glutamatergic metabolites in vivo. Here we briefly review the 1H-MRS studies that have explored relationships between glutamatergic metabolites, symptoms and cognitive function in clinical samples. While some of these studies suggest that more severe symptoms may be associated with elevated glutamatergic function in the anterior cingulate, studies in larger patient samples selected on the basis of symptom severity are required.

Unusual differences in the reactivity of glutamic and aspartic acid in oxidative decarboxylation reactions

NARCIS (Netherlands)

But, Andrada; Wijst, van der Evie; Notre, le Jerome; Wever, Ron; Sanders, Johan P.M.; Bitter, Johannes H.; Scott, Elinor L.

2017-01-01

Amino acids are potential substrates to replace fossil feedstocks for the synthesis of nitriles via oxidative decarboxylation using vanadium chloroperoxidase (VCPO), H₂O₂ and bromide. Here the conversion of glutamic acid (Glu) and aspartic acid (Asp) was investigated. It was

Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons

Science.gov (United States)

Zhou, Chengwen; Sun, Hongyu; Klein, Peter M.; Jensen, Frances E.

2015-01-01

Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48–96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg2+ sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID:26441533

Molecular pharmacology of homologues of ibotenic acid at cloned metabotropic glutamic acid receptors

DEFF Research Database (Denmark)

Bräuner-Osborne, Hans; Nielsen, B; Krogsgaard-Larsen, P

1998-01-01

We have studied the effects of the enantiomers of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) and analogues substituted with a methyl, bromo or butyl group in the four position of the ring at cloned metabotropic glutamate (mGlu) receptors expressed in Chinese hamster...... ovary (CHO) cells. In contrast to the parent compound ibotenic acid, which is a potent group I and II agonist, the (S)-forms of homoibotenic acid and its analogues are selective and potent group I antagonists whereas the (R)-forms are inactive both as agonists and antagonists at group I, II, and III m......Glu receptors. Interestingly, (S)-homoibotenic acid and the analogues display equal potency at both mGlu1alpha and mGlu5a with Ki values in the range of 97 to 490 microM, (S)-homoibotenic acid and (S)-2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid [(S)-4-butylhomoibotenic acid] displaying the lowest...

Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors

Energy Technology Data Exchange (ETDEWEB)

Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.; Schulten, Klaus; Mayer, Mark L. (UIUC); (NIH)

2008-10-27

NR3 subtype glutamate receptors have a unique developmental expression profile, but are the least well-characterized members of the NMDA receptor gene family, which have key roles in synaptic plasticity and brain development. Using ligand binding assays, crystallographic analysis, and all atom MD simulations, we investigate mechanisms underlying the binding by NR3A and NR3B of glycine and D-serine, which are candidate neurotransmitters for NMDA receptors containing NR3 subunits. The ligand binding domains of both NR3 subunits adopt a similar extent of domain closure as found in the corresponding NR1 complexes, but have a unique loop 1 structure distinct from that in all other glutamate receptor ion channels. Within their ligand binding pockets, NR3A and NR3B have strikingly different hydrogen bonding networks and solvent structures from those found in NR1, and fail to undergo a conformational rearrangement observed in NR1 upon binding the partial agonist ACPC. MD simulations revealed numerous interdomain contacts, which stabilize the agonist-bound closed-cleft conformation, and a novel twisting motion for the loop 1 helix that is unique in NR3 subunits.

Novel Fluorine-Containing NMDA Antagonists for Brain Imaging: In Vitro Evaluation

Energy Technology Data Exchange (ETDEWEB)

Alvarado, M.; Biegon, A.

2001-01-01

The NMDA receptor has been implicated in neuronal death following stroke, brain injury and neurodegenerative disorders (e.g. Alzheimer's, Parkinson's and Huntington's disease) and in physiological functions (e.g. memory and cognition). Non-competitive antagonists, such as MK- 801 and CNS-1102, that block the action of glutamate at the NMDA receptor have been shown to be neuroprotective by blocking the influx of calcium into the cells. As a result, they are being considered as therapeutic agents for the above mentioned diseases. Several Fluorine-containing novel analogs of NMDA channel blockers have been synthesized and evaluated in search of a compound suitable for 18F labeling and Positron Emission Tomography (PET). Based on in vitro binding assay studies on rat brain membranes, the novel compounds examined displayed a range of affinities. Preliminary analyses indicated that chlorine is the best halogen on the ring, and that ethyl fluoro derivatives are more potent than methyl-fluoro compounds. Further analysis based on autoradiography will be needed to examine the regional binding characteristics of the novel compounds examined in this study. Labeling with 18F will allow the use of these compounds in humans, generating new insights into mechanisms and treatment of diseases involving malfunction of the glutamatergic system in the brain.

Use of Nonspecific, Glutamic Acid-Free, Media and High Glycerol or High Amylase as Inducing Parameters for Screening Bacillus Isolates Having High Yield of Polyglutamic Acid.

Science.gov (United States)

Baxi, Nandita N

2014-01-01

Out of fifty-five Bacillus isolates obtained from ten different regional locations and sources, seven showed the ability to consistently produce specific extracellular polymeric substance (EPS) on rich as well as synthetic but nonspecific media which did not contain glutamic acid. The isolates were identified as either Bacillus licheniformis or Bacillus subtilis. The EPS from all isolates was resistant to alpha protease, proteinase K, and was thus of high molecular weight. Further it was detected after SDS-PAGE by methylene blue but not by coomassie blue R staining as in case of proteins with high proportion of acidic amino acids. Cell-free EPS, after acid hydrolysis, showed absence of carbohydrates and presence of only glutamic acid. Thus the native the EPS from all seven isolates was confirmed to be gamma polyglutamic acid (PGA) and not exopolysaccharide. The Bacillus isolate T which produced maximum polymer on all media tested had higher amylase: protease activity as compared to other strains. If inoculum was developed in rich medium as compared to synthetic medium, the PGA produced increased by twofold in the subsequent synthetic production medium. Similarly, use of inoculum consisting of young and vegetative cells also increased the PGA production by twofold though amount of inoculum did not affect yield of PGA. Though PGA was produced in even in the absence of glutamic acid supplementation in the production medium by all isolates, the yield of PGA increased by fourfold in the presence glutamic acid and the maximum yield was 30 g/l for isolate K. The supplementation of glutamine instead of glutamic acid into the medium caused an increase in the viscosity of the non-Newtonian solution of PGA.

Development of a Method to Isolate Glutamic Acid from Foodstuffs for a Precise Determination of Their Stable Carbon Isotope Ratio.

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Kobayashi, Kazuhiro; Tanaka, Masaharu; Yatsukawa, Yoichi; Tanabe, Soichi; Tanaka, Mitsuru; Ohkouchi, Naohiko

2018-01-01

Recent growing health awareness is leading to increasingly conscious decisions by consumers regarding the production and traceability of food. Stable isotopic compositions provide useful information for tracing the origin of foodstuffs and processes of food production. Plants exhibit different ratios of stable carbon isotopes (δ 13 C) because they utilized different photosynthetic (carbon fixation) pathways and grow in various environments. The origins of glutamic acid in foodstuffs can be differentiated on the basis of these photosynthetic characteristics. Here, we have developed a method to isolate glutamic acid in foodstuffs for determining the δ 13 C value by elemental analyzer-isotope-ratio mass spectrometry (EA/IRMS) without unintended isotopic fractionation. Briefly, following acid-hydrolysis, samples were defatted and passed through activated carbon and a cation-exchange column. Then, glutamic acid was isolated using preparative HPLC. This method is applicable to measuring, with a low standard deviation, the δ 13 C values of glutamic acid from foodstuffs derived from C3 and C4 plants and marine algae.

Synthesis and pharmacological characterization at glutamate receptors of the four enantiopure isomers of tricholomic acid

DEFF Research Database (Denmark)

Pinto, Andrea; Conti, Paola; De Amici, Marco

2008-01-01

of the studied amino acids reflect the relationship between the activity/selectivity and the stereochemistry of the two stereogenic centers: while the (2 S,5' S) stereoisomer is an agonist at the AMPA and KA receptors, its (2 R,5' R) enantiomer interacts selectively with the NMDA receptors; the (2 S,5' R...

Effect of L-glutamic acid on the positive electrolyte for all-vanadium redox flow battery

International Nuclear Information System (INIS)

Liang, Xinxing; Peng, Sui; Lei, Ying; Gao, Chao; Wang, Nanfang; Liu, Suqin; Fang, Dong

2013-01-01

Highlights: ► Amino acid is used as additive for all-vanadium redox flow battery. ► The additive can significantly improve performance of positive electrolyte. ► Mechanism for the improvement is investigated. -- Abstract: L-Glutamic acid is used as an additive for the positive electrolyte of all-vanadium redox flow battery (VRFB), and its effect on the thermal stability and electrochemical activity is investigated. It is found that the addition of L-glutamic can significantly alleviate the precipitation of V 2 O 5 from positive electrolyte. The conservation rate of V(V) ion can be as high as 58% after 2 M V(V) solution being kept in 40 °C for 89 h. Besides, L-glutamic can also improve the mass transport and electrochemical performance of anolyte. A high coulombic efficiency of over 95% and energy efficiency of 74% are obtained. XPS spectra illustrate that L-glutamic can react with the surface of carbon felt electrode and introduce more oxygen-containing and nitrogen-containing groups, which should be responsible for the improvement of electrochemical performance

The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain

DEFF Research Database (Denmark)

Kristensen, P J; Gegelashvili, G; Munro, G

2017-01-01

-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.......BACKGROUND: Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which......, ceftriaxone, displays analgesic effects in rodent chronic pain models. METHODS: Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain...

Supplementation of diets for weaned piglets withL-Valine and L-Glutamine+ L-Glutamic acid

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Naiara Diedrich Rodrigues

2015-10-01

Full Text Available The objective of this study was to evaluate the effects of supplementation of diets for weaned piglets with L-valine and L-glutamine + L-glutamic acid on performance, frequency of diarrhea, organ weight, digesta pH, intestinal morphology, and economic viability. Seventy-two piglets with a live weight of 7.53 ± 0.84 kg and 24 days of age were used. The animals were submitted to the following four treatments from 24 to 46 days of age: diet not supplemented with amino acids (control diet, CD; diet supplemented with glutamine + glutamic acid (GD; diet supplemented with glutamine + glutamic acid + valine (GVD, and diet supplemented with valine (VD. Two sequential phases (pre-initial I and pre-initial II with a duration of 12 and 11 days, respectively, were established. A completely randomized design, consisting of six repetitions and three pigs per experimental unit, was used. Nine days after weaning, at 32 days of age, a piglet per pen was slaughtered for the evaluation of organ weight, digesta pH and intestinal morphology. All animals received a single diet from days 47 to 65. No effects on performance were observed during the pre-initial phases I and II; however, when the whole study period was considered (24 to 65 days of age, piglets fed GVD consumed less feed and exhibited better feed conversion than animals of the VD group. With respect to morphometric parameters, GD provided a greater ileal crypt depth than CD and VD. There was an economic advantage of diets supplemented with L-valine and L-glutamine + L-glutamic acid, validating their use in diets for weaned piglets until 46 days of age.

Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones.

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Crossthwaite, Andrew J; Valli, Haseeb; Williams, Robert J

2004-03-01

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.

Influence of additive L-phenylalanine on stabilization of metastable α-form of L-glutamic acid in cooling crystallization

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Quang, Khuu Chau; Nhan, Le Thi Hong; Huyen, Trinh Thi Thanh; Tuan, Nguyen Anh

2017-09-01

The influence of additive amino acid L-phenylalanine on stabilization of metastable α-form of L-glutamic acid was investigated in cooling crystallization. The present study found that the additive L-phenylalanine could be used to stabilize the pure metastable α-form in L-glutamic acid crystallization, where the additive concentration of 0.05-0.1 (g/L) was sufficient to stabilize the 100% wt metastable α-form in solid product at L-glutamic acid concentration of 30-45 (g/L). Additionally, the present results indicated that the adsorption of additive L-phenylalanine on the (001) surface of α-form was more favorable than that of the β-form molecular, so the nucleation sites of stable β-form was occupied by additive molecular, which resulted in inhibition of nucleation and growth of β-form, allowing stabilization of metastable α-form.

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

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Dickenson Anthony H

2009-02-01

Full Text Available Abstract Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1 has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

Science.gov (United States)

Nguyen, David; Deng, Ping; Matthews, Elizabeth A; Kim, Doo-Sik; Feng, Guoping; Dickenson, Anthony H; Xu, Zao C; Luo, Z David

2009-01-01

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous

Capillary electrophoresis tandem mass spectrometry determination of glutamic acid and homocysteine's metabolites: Potential biomarkers of amyotrophic lateral sclerosis.

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Cieslarova, Zuzana; Lopes, Fernando Silva; do Lago, Claudimir Lucio; França, Marcondes Cavalcante; Colnaghi Simionato, Ana Valéria

2017-08-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons, leading to muscle atrophy, paralysis, and death caused by respiratory failure or infectious complications. Altered levels of homocysteine, cysteine, methionine, and glutamic acid have been observed in plasma of ALS patients. In this context, a method for determination of these potential biomarkers in plasma by capillary electrophoresis tandem mass spectrometry (CE-MS/MS) is proposed herein. Sample preparation was carefully investigated, since sulfur-containing amino acids may interact with plasma proteins. Owing to the non-thiol sulfur atom in methionine, it was necessary to split sample preparation into two methods: i) determination of homocysteine and cysteine as S-acetyl amino acids; ii) determination of glutamic acid and methionine. All amino acids were separated within 25min by CE-MS/MS using 5molL -1 acetic acid as background electrolyte and 5mmolL -1 acetic acid in 50% methanol/H 2 O (v/v) as sheath liquid. The proposed CE-MS/MS method was validated, presenting RSD values below 6% and 11% for intra- and inter-day precision, respectively, for the middle concentration level within the linear range. The limits of detection ranged from 35 (homocysteine) to 268nmolL -1 (glutamic acid). The validated method was applied to the analysis of plasma samples from a group of healthy individuals and patients with ALS, showing the potential of glutamic acid and homocysteine metabolites as biomarkers of ALS. Copyright © 2017 Elsevier B.V. All rights reserved.

Group I mGlu receptors potentiate synaptosomal [3H]glutamate release independently of exogenously applied arachidonic acid

International Nuclear Information System (INIS)

Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J.

1999-01-01

In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [ 3 H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 μM) increased 4AP-evoked [ 3 H]glutamate release (143.32±2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC 50 =1.60±0.25 μM; E max =147.61±10.96% control) 4AP-evoked [ 3 H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu 1 receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 μM) and was BSA-insensitive. The selective mGlu 5 receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300μM) was without effect. DHPG (100 μM) also potentiated both 30 mM and 50 mM K + -evoked [ 3 H]glutamate release (121.60±12.77% and 121.50±4.45% control, respectively). DHPG (100 μM) failed to influence both 4AP-stimulated 45 Ca 2+ influx and 50 mM K + -induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A 1 receptor, group II/III mGlu receptors or GABA B receptor activity is unlikely since 4AP-evoked [ 3 H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-α-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu 1 receptor-like' receptor potentiates [ 3 H]glutamate release from cerebrocortical synaptosomes in the absence of exogenously applied arachidonic acid. This PKC dependent effect is unlikely to be via modulation of synaptosomal membrane

Dietary intakes of glutamic acid and glycine are associated with stroke mortality in Japanese adults.

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Nagata, Chisato; Wada, Keiko; Tamura, Takashi; Kawachi, Toshiaki; Konishi, Kie; Tsuji, Michiko; Nakamura, Kozue

2015-04-01

Dietary intakes of glutamic acid and glycine have been reported to be associated with blood pressure. However, the link between intakes of these amino acids and stroke has not been studied. We aimed to examine the association between glutamic acid and glycine intakes and the risk of mortality from stroke in a population-based cohort study in Japan. The analyses included 29,079 residents (13,355 men and 15,724 women) of Takayama City, Japan, who were aged 35-101 y and enrolled in 1992. Their body mass index ranged from 9.9 to 57.4 kg/m(2). Their diets were assessed by a validated food frequency questionnaire. Deaths from stroke were ascertained over 16 y. During follow-up, 677 deaths from stroke (328 men and 349 women) were identified. A high intake of glutamic acid in terms of a percentage of total protein was significantly associated with a decreased risk of mortality from total stroke in women after controlling for covariates; the HR (95% CI) for the highest vs. lowest quartile was 0.72 (0.53, 0.98; P-trend: 0.03). Glycine intake was significantly associated with an increased risk of mortality from total and ischemic stroke in men without history of hypertension at baseline; the HRs (95% CIs) for the highest vs. lowest tertile were 1.60 (0.97, 2.51; P-trend: 0.03) and 1.88 (1.01, 3.52; P-trend: 0.02), respectively. There was no association between animal or vegetable protein intake and mortality from total and any subtype of stroke. The data suggest that glutamic acid and glycine intakes may be associated with risk of stroke mortality. Given that this is an initial observation, our results need to be confirmed. © 2015 American Society for Nutrition.

The periplasmic transaminase PtaA of Pseudomonas fluorescens converts the glutamic acid residue at the pyoverdine fluorophore to α-ketoglutaric acid.

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Ringel, Michael T; Dräger, Gerald; Brüser, Thomas

2017-11-10

The periplasmic conversion of ferribactin to pyoverdine is essential for siderophore biogenesis in fluorescent pseudomonads, such as pathogenic Pseudomonas aeruginosa or plant growth-promoting Pseudomonas fluorescens The non-ribosomal peptide ferribactin undergoes cyclizations and oxidations that result in the fluorophore, and a strictly conserved fluorophore-bound glutamic acid residue is converted to a range of variants, including succinamide, succinic acid, and α-ketoglutaric acid residues. We recently discovered that the pyridoxal phosphate-containing enzyme PvdN is responsible for the generation of the succinamide, which can be hydrolyzed to succinic acid. Based on this, a distinct unknown enzyme was postulated to be responsible for the conversion of the glutamic acid to α-ketoglutaric acid. Here we report the identification and characterization of this enzyme in P. fluorescens strain A506. In silico analyses indicated a periplasmic transaminase in fluorescent pseudomonads and other proteobacteria that we termed PtaA for " p eriplasmic t ransaminase A " An in-frame-deleted ptaA mutant selectively lacked the α-ketoglutaric acid form of pyoverdine, and recombinant PtaA complemented this phenotype. The ptaA / pvdN double mutant produced exclusively the glutamic acid form of pyoverdine. PtaA is homodimeric and contains a pyridoxal phosphate cofactor. Mutation of the active-site lysine abolished PtaA activity and affected folding as well as Tat-dependent transport of the enzyme. In pseudomonads, the occurrence of ptaA correlates with the occurrence of α-ketoglutaric acid forms of pyoverdines. As this enzyme is not restricted to pyoverdine-producing bacteria, its catalysis of periplasmic transaminations is most likely a general tool for specific biosynthetic pathways. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory.

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Alaghband, Yasaman; Marshall, John F

2013-04-01

Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition. The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories. For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval. Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals' preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement. Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.

The role of excitatory amino acids and substance P in the mediation of the cough reflex within the nucleus tractus solitarii of the rabbit.

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Mutolo, Donatella; Bongianni, Fulvia; Fontana, Giovanni A; Pantaleo, Tito

2007-09-28

We hypothesized that cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit is primarily mediated by glutamatergic neurotransmission at the level of the caudal portions of the medial subnucleus of the nucleus tractus solitarii (NTS) and the lateral commissural NTS where cough-related afferents terminate, and that this reflex is potentiated by local release of substance P. To test our hypothesis, we performed bilateral microinjections (30-50 nl) of ionotropic glutamate receptor antagonists or substance P into these locations in pentobarbitone anaesthetized, spontaneously breathing rabbits. Blockade of NMDA and non-NMDA receptors by 50mM kynurenic acid abolished the cough reflex without affecting the Breuer-Hering inflation reflex or the pulmonary chemoreflex. Blockade of non-NMDA receptors using 10mM CNQX or 5mM NBQX caused identical effects. Blockade of NMDA receptors by 10mM D-AP5 strongly reduced, but did not abolish cough responses. Microinjections of 1mM substance P increased peak and rate of rise of abdominal muscle activity as well as cough number. These results are the first to provide evidence that ionotropic glutamate receptors, especially non-NMDA receptors, located within specific regions of NTS are primarily involved in the mediation of cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit. Present findings on substance P cough-enhancing effects extend previous observations and are relevant to the tachykinin-mediated central sensitization of the cough reflex. They also may provide hints for further studies on centrally acting antitussive drugs.

The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

International Nuclear Information System (INIS)

Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina; Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya; Pessoa-Pureur, Regina

2014-01-01

Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to 32 P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca 2+ /calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca 2+ quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca 2+ influx through voltage-dependent Ca 2+ channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative disorders. - Highlights: �

Acacetin inhibits glutamate release and prevents kainic acid-induced neurotoxicity in rats.

Directory of Open Access Journals (Sweden)

Tzu-Yu Lin

Full Text Available An excessive release of glutamate is considered to be a molecular mechanism associated with several neurological diseases that causes neuronal damage. Therefore, searching for compounds that reduce glutamate neurotoxicity is necessary. In this study, the possibility that the natural flavone acacetin derived from the traditional Chinese medicine Clerodendrum inerme (L. Gaertn is a neuroprotective agent was investigated. The effect of acacetin on endogenous glutamate release in rat hippocampal nerve terminals (synaptosomes was also investigated. The results indicated that acacetin inhibited depolarization-evoked glutamate release and cytosolic free Ca(2+ concentration ([Ca(2+]C in the hippocampal nerve terminals. However, acacetin did not alter synaptosomal membrane potential. Furthermore, the inhibitory effect of acacetin on evoked glutamate release was prevented by the Cav2.2 (N-type and Cav2.1 (P/Q-type channel blocker known as ω-conotoxin MVIIC. In a kainic acid (KA rat model, an animal model used for excitotoxic neurodegeneration experiments, acacetin (10 or 50 mg/kg was administrated intraperitoneally to the rats 30 min before the KA (15 mg/kg intraperitoneal injection, and subsequently induced the attenuation of KA-induced neuronal cell death and microglia activation in the CA3 region of the hippocampus. The present study demonstrates that the natural compound, acacetin, inhibits glutamate release from hippocampal synaptosomes by attenuating voltage-dependent Ca(2+ entry and effectively prevents KA-induced in vivo excitotoxicity. Collectively, these data suggest that acacetin has the therapeutic potential for treating neurological diseases associated with excitotoxicity.

Environmental Comparison of Biobased Chemicals from Glutamic Acid with Their Petrochemical Equivalents

NARCIS (Netherlands)

Lammens, T.M.; Potting, J.; Sanders, J.P.M.; Boer, de I.J.M.

2011-01-01

Glutamic acid is an important constituent of waste streams from biofuels production. It is an interesting starting material for the synthesis of biobased chemicals, thereby decreasing the dependency on fossil fuels. The objective of this paper was to compare the environmental impact of four biobased

Environmental comparison of biobased chemicals from glutamic acid with their petrochemical equivalents

NARCIS (Netherlands)

Lammens, T.M.; Potting, J.; Sanders, J.P.M.; Boer, de I.J.M.

2012-01-01

Glutamic acid is an important constituent of waste streams from biofuels production. It is an interesting starting material for the synthesis of biobased chemicals, thereby decreasing the dependency on fossil fuels. The objective of this paper was to compare the environmental impact of four biobased

NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala.

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Kenny, Paul J; Chartoff, Elena; Roberto, Marisa; Carlezon, William A; Markou, Athina

2009-01-01

Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.

Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

DEFF Research Database (Denmark)

Kofod, Hans; Lernmark, A; Hedeskov, C J

1986-01-01

Column perifusion of mouse pancreatic islets was used to study the ability of amino acids and their methyl esters to influence insulin release and activate islet glutamate dehydrogenase activity. In the absence of L-glutamine, L-serine and the methyl ester of L-phenylalanine, but neither L...... glutamate dehydrogenase activity showed that only the two methyl esters of L-phenylalanine and L-serine activated the enzyme. It is concluded that the mechanism by which methyl esters of amino acids potentiate insulin release is most likely to be mediated by the activation of pancreatic beta-cell glutamate...

Current and calcium responses to local activation of axonal NMDA receptors in developing cerebellar molecular layer interneurons.

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Bénédicte Rossi

Full Text Available In developing cerebellar molecular layer interneurons (MLIs, NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca(2+ channels (VDCCs. Using Ca(2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg(2+ or by the addition of APV. Similar paradigms yielded restricted Ca(2+ transients in interneurons loaded with a Ca(2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca(2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca(2+-induced Ca(2+ release process mediated by presynaptic Ca(2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca(2+-mediated synaptic plasticity.

Neuromodulation by Mg2+ and polyamines of excitatory amino acid currents in rodent neurones in culture.

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Kumamoto, E

1996-12-01

Excitatory amino-acid currents in rodent central neurones are mediated by the activation of glutamate receptors. Ionotropic types of the receptors are divided into alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors, and the former two are collectively called non-NMDA receptors. The NMDA receptor is modulated by a number of endogenous neuromodulators including Mg2+, polyamines, glycine and protons in extracellular solutions. Although it has been generally thought that each of the neuromodulators acts on a distinct site in the NMDA receptor, recent studies have revealed that these actions may be not necessarily independent of each other. The NMDA receptor response is not only inhibited but also potentiated by Mg2+, and the latter action is due to an interaction of a Mg2+ site with either glycine- or proton-binding site. In the presence of polyamines, a tonic inhibition by protons of the NMDA receptor response is relieved, resulting in a potentiation of the response. Alternatively, it has been recently revealed that there are some subtypes of non-NMDA receptors which are negatively modulated by polyamines in either extra- or intra cellular solutions. The difference in polyamine sensitivity among non-NMDA receptors is attributed to a distinction in their constituted subunits. The inhibition of non-NMDA receptor by intracellular polyamines results in inward rectification of the current-voltage relation which is not seen for polyamine-insensitive ones. This polyamine action is not mimicked by intracellular Mg2+.

Co-Production of Nattokinase and Poly (γ-Glutamic Acid Under Solid-State Fermentation Using Soybean and Rice Husk

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Guangjun Nie

2015-10-01

Full Text Available ABSTRACTThe aim of this work was to study the co-production of nattokinase and poly (γ-glutamic acid by Bacillus subtilis natto with soybean and rice husk under solid-state fermentation (SSF. The results showed that the size of soybean particle and rice husk significantly improved the co-production of nattokinase and poly (γ-glutamic acid, yielding 2503.4 IU/gs and 320 mg/gs, respectively in the improved culture medium composed of 16.7% soybean flour and 13.3% rice husk with 70% water content. The yields increased by approximate 7- and 2-fold factor relative to their original ones. Thus, the co-production of nattokinase and poly (γ-glutamic acid under SSF could be considered as an efficient method to exploit agro-residues for economical production of some higher-value products.

Circadian Regulation of Glutamate Transporters

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Donají Chi-Castañeda

2018-06-01

Full Text Available L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS. This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases. Increasing evidence indicates glutamate transporters are controlled by the circadian system in direct and indirect manners, so in this contribution we focus on the mechanisms of circadian regulation (transcriptional, translational, post-translational and post-transcriptional regulation of glutamate transport in neuronal and glial cells, and their consequence in brain function.

Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

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Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

2017-11-01

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

An NMR-based metabolomic approach to investigate the effects of supplementation with glutamic acid in piglets challenged with deoxynivalenol.

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Wu, Miaomiao; Xiao, Hao; Ren, Wenkai; Yin, Jie; Hu, Jiayu; Duan, Jielin; Liu, Gang; Tan, Bie; Xiong, Xia; Oso, Abimbola Oladele; Adeola, Olayiwola; Yao, Kang; Yin, Yulong; Li, Tiejun

2014-01-01

Deoxynivalenol (DON) has various toxicological effects in humans and pigs that result from the ingestion of contaminated cereal products. This study was conducted to investigate the protective effects of dietary supplementation with glutamic acid on piglets challenged with DON. A total of 20 piglets weaned at 28 d of age were randomly assigned to receive 1 of 4 treatments (5 piglets/treatment): 1) basal diet, negative control (NC); 2) basal diet +4 mg/kg DON (DON); 3) basal diet +2% (g/g) glutamic acid (GLU); 4) basal diet +4 mg/kg DON +2% glutamic acid (DG). A 7-d adaptation period was followed by 30 days of treatment. A metabolite analysis using nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomic technology and the determination of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities for plasma, as well as the activity of Caspase-3 and the proliferation of epithelial cells were conducted. The results showed that contents of low-density lipoprotein, alanine, arginine, acetate, glycoprotein, trimethylamine-N-oxide (TMAO), glycine, lactate, and urea, as well as the glutamate/creatinine ratio were higher but high-density lipoprotein, proline, citrate, choline, unsaturated lipids and fumarate were lower in piglets of DON treatment than that of NC treatment (Pglutamic acid increased the plasma concentrations of proline, citrate, creatinine, unsaturated lipids, and fumarate, and decreased the concentrations of alanine, glycoprotein, TMAO, glycine, and lactate, as well as the glutamate/creatinine ratio (Pglutamic acid to DON treatment increased the plasma activities of SOD and GSH-Px and the proliferating cell nuclear antigen (PCNA) labeling indexes for the jejunum and ileum (Pglutamic acid has the potential to repair the injuries associated with oxidative stress as well as the disturbances of energy and amino acid metabolism induced by DON.

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

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Alagarsamy, Sudar; Saugstad, Julie; Warren, Lee; Mansuy, Isabelle M.; Gereau, Robert W.; Conn, P. Jeffrey

2010-01-01

Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor. 2005 Elsevier Ltd. All rights reserved. PMID:16005030

Fyziologie glutamátu, dlouhodobá potenciace, schizofrenie a paměť

Czech Academy of Sciences Publication Activity Database

Stuchlík, Aleš; Svojanovská, Markéta

2014-01-01

Roč. 63, č. 2 (2014), s. 84-91 ISSN 1210-6313 R&D Projects: GA ČR(CZ) GA14-03627S; GA MZd(CZ) NT13386; GA MŠk(CZ) LH14053 Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : glutamate * memory * NMDA receptors Subject RIV: FH - Neurology

Brain infection with Staphylococcus aureus leads to high extracellular levels of glutamate, aspartate, γ-aminobutyric acid, and zinc.

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Hassel, Bjørnar; Dahlberg, Daniel; Mariussen, Espen; Goverud, Ingeborg Løstegaard; Antal, Ellen-Ann; Tønjum, Tone; Maehlen, Jan

2014-12-01

Staphylococcal brain infections may cause mental deterioration and epileptic seizures, suggesting interference with normal neurotransmission in the brain. We injected Staphylococcus aureus into rat striatum and found an initial 76% reduction in the extracellular level of glutamate as detected by microdialysis at 2 hr after staphylococcal infection. At 8 hr after staphylococcal infection, however, the extracellular level of glutamate had increased 12-fold, and at 20 hr it had increased >30-fold. The extracellular level of aspartate and γ-aminobutyric acid (GABA) also increased greatly. Extracellular Zn(2+) , which was estimated at ∼2.6 µmol/liter in the control situation, was increased by 330% 1-2.5 hr after staphylococcal infection and by 100% at 8 and 20 hr. The increase in extracellular glutamate, aspartate, and GABA appeared to reflect the degree of tissue damage. The area of tissue damage greatly exceeded the area of staphylococcal infiltration, pointing to soluble factors being responsible for cell death. However, the N-methyl-D-aspartate receptor antagonist MK-801 ameliorated neither tissue damage nor the increase in extracellular neuroactive amino acids, suggesting the presence of neurotoxic factors other than glutamate and aspartate. In vitro staphylococci incubated with glutamine and glucose formed glutamate, so bacteria could be an additional source of infection-related glutamate. We conclude that the dramatic increase in the extracellular concentration of neuroactive amino acids and zinc could interfere with neurotransmission in the surrounding brain tissue, contributing to mental deterioration and a predisposition to epileptic seizures, which are often seen in brain abscess patients. © 2014 Wiley Periodicals, Inc.

Utilization of barley or wheat bran to bioconvert glutamate to γ-aminobutyric acid (GABA).

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Jin, Wen-Jie; Kim, Min-Ju; Kim, Keun-Sung

2013-09-01

This study deals with the utilization of agro-industrial wastes created by barley and wheat bran in the production of a value-added product, γ-aminobutyric acid (GABA). The simple and eco-friendly reaction requires no pretreatment or microbial fermentation steps but uses barley or wheat bran as an enzyme source, glutamate as a substrate, and pyridoxal 5'-phosphate (PLP) as a cofactor. The optimal reaction conditions were determined on the basis of the temperatures and times used for the decarboxylation reactions and the initial concentrations of barley or wheat bran, glutamate, and PLP. The optimal reactions produced 9.2 mM of GABA from 10 mM glutamate, yielding a 92% GABA conversion rate, when barley bran was used and 6.0 mM of GABA from 10 mM glutamate, yielding a 60% GABA conversion rate, when wheat bran was used. The results imply that barley bran is more efficient than wheat bran in the production of GABA. © 2013 Institute of Food Technologists®

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population.

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Featherstone, Robert E; Shin, Rick; Kogan, Jeffrey H; Liang, Yuling; Matsumoto, Mitsuyuki; Siegel, Steven J

2015-01-01

Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia. Copyright �

3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate

DEFF Research Database (Denmark)

Storgaard, J; Kornblit, B T; Zimmer, J

2000-01-01

of lactate dehydrogenase in the medium and glutamic acid decarboxylase in tissue homogenates. 3-NPA toxicity (25-100 microM in 5 mM glucose, 24-48 h) appeared to be highly dependent on culture medium glucose levels. 3-NPA treatment caused also a dose-dependent lactate increase, reaching a maximum......Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay...... of threefold increase above control at 100 microM. Both a high dose of glutamate (5 mM) and glutamate uptake blockade by dl-threo-beta-hydroxyaspartate potentiated 3-NPA neurotoxicity in corticostriatal slice cultures. Furthermore, striatum from corticostriatal cocultures was more sensitive to 3-NPA than...

Glutamic Acid Residues in HIV-1 p6 Regulate Virus Budding and Membrane Association of Gag.

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Friedrich, Melanie; Setz, Christian; Hahn, Friedrich; Matthaei, Alina; Fraedrich, Kirsten; Rauch, Pia; Henklein, Petra; Traxdorf, Maximilian; Fossen, Torgils; Schubert, Ulrich

2016-04-25

The HIV-1 Gag p6 protein regulates the final abscission step of nascent virions from the cell membrane by the action of its two late (L-) domains, which recruit Tsg101 and ALIX, components of the ESCRT system. Even though p6 consists of only 52 amino acids, it is encoded by one of the most polymorphic regions of the HIV-1 gag gene and undergoes various posttranslational modifications including sumoylation, ubiquitination, and phosphorylation. In addition, it mediates the incorporation of the HIV-1 accessory protein Vpr into budding virions. Despite its small size, p6 exhibits an unusually high charge density. In this study, we show that mutation of the conserved glutamic acids within p6 increases the membrane association of Pr55 Gag followed by enhanced polyubiquitination and MHC-I antigen presentation of Gag-derived epitopes, possibly due to prolonged exposure to membrane bound E3 ligases. The replication capacity of the total glutamic acid mutant E0A was almost completely impaired, which was accompanied by defective virus release that could not be rescued by ALIX overexpression. Altogether, our data indicate that the glutamic acids within p6 contribute to the late steps of viral replication and may contribute to the interaction of Gag with the plasma membrane.

NOVEL POLY-GLUTAMIC ACID FUNCTIONALIZED MICROFILTRATION MEMBRANES FOR SORPTION OF HEAVY METALS AT HIGH CAPACITY

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Various sorbent/ion exchange materials have been reported in the literature for metal ion entrapment. We have developed a highly innovative and new approach to obtain high metal pick-up utilizing poly-amino acids (poly-L-glutamic acid, 14,000 MW) covalently attached to membrane p...

Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain.

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Carla M Yuede

2010-06-01

Full Text Available Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia.We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP, or saline, on postnatal day 2 (P2 or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7.These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathological and neurobehavioral consequences than a single treatment.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

Science.gov (United States)

Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

2007-06-01

Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

Srovnání vlivu systémové aplikace non-kompetitivních a use-dependentních NMDA antagonistů na lokomoční aktivitu a kognitivní funkce u laboratorního potkana

Czech Academy of Sciences Publication Activity Database

Valeš, Karel; Rambousek, Lukáš; Stuchlík, Aleš; Chodounská, Hana; Vyklický ml., Ladislav

2010-01-01

Roč. 14, Suppl.2 (2010), s. 26-30 ISSN 1211-7579 R&D Projects: GA MŠk(CZ) 1M0517; GA MZd(CZ) NR9180; GA MZd(CZ) NS10365; GA ČR(CZ) GA203/08/1498 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z40550506 Keywords : NMDA receptor * glutamate excitotoxicity * NMDA antagonists Subject RIV: FH - Neurology

Central transport and distribution of labelled glutamic and aspartic acids to the cochlear nucleus in cats. An autoradiographic study

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Kane, E S [University of Massachusetts Medical School, Worcester, MA (USA). Dept. of Anatomy

1979-01-01

Tritiated L-glutamic acid or L-aspartic acid was injected unilaterally into the cochleas of adult cats, and 4 h-7 days later the localization of label was studied by light-microscopic autoradiography in sections of the brain stem. Consistent differences in labelling after glutamate and after aspartate suggest differences in their uptake, metabolic conversion and/or transport to the cochlear nucleus by cochlear fibers. The morphological differences shown here agree with the distribution of those two amino acids in the cat cochlear nucleus as shown by microchemical analyses.

Delayed translocation of NGFI-B/RXR in glutamate stimulated neurons allows late protection by 9-cis retinoic acid

International Nuclear Information System (INIS)

Mathisen, Gro H.; Fallgren, Asa B.; Strom, Bjorn O.; Boldingh Debernard, Karen A.; Mohebi, Beata U.; Paulsen, Ragnhild E.

2011-01-01

Highlights: → NGFI-B and RXR translocate out of the nucleus after glutamate treatment. → Arresting NGFI-B/RXR in the nucleus protects neurons from excitotoxicity. → Late protection by 9-cis RA is possible due to a delayed translocation of NGFI-B/RXR. -- Abstract: Nuclear receptor and apoptosis inducer NGFI-B translocates out of the nucleus as a heterodimer with RXR in response to different apoptosis stimuli, and therefore represents a potential pharmacological target. We found that the cytosolic levels of NGFI-B and RXRα were increased in cultures of cerebellar granule neurons 2 h after treatment with glutamate (excitatory neurotransmitter in the brain, involved in stroke). To find a time-window for potential intervention the neurons were transfected with gfp-tagged expressor plasmids for NGFI-B and RXR. The default localization of NGFI-Bgfp and RXRgfp was nuclear, however, translocation out of the nucleus was observed 2-3 h after glutamate treatment. We therefore hypothesized that the time-window between treatment and translocation would allow late protection against neuronal death. The RXR ligand 9-cis retinoic acid was used to arrest NGFI-B and RXR in the nucleus. Addition of 9-cis retinoic acid 1 h after treatment with glutamate reduced the cytosolic translocation of NGFI-B and RXRα, the cytosolic translocation of NGFI-Bgfp observed in live neurons, as well as the neuronal death. However, the reduced translocation and the reduced cell death were not observed when 9-cis retinoic acid was added after 3 h. Thus, late protection from glutamate induced death by addition of 9-cis retinoic acid is possible in a time-window after apoptosis induction.

Regulated appearance of NMDA receptor subunits and channel functions during in vitro neuronal differentiation

NARCIS (Netherlands)

Jelitai, Márta; Schlett, Katalin; Varju, Patrícia; Eisel, Ulrich; Madarász, Emília

The schedule of NMDA receptor subunit expression and the appearance of functional NMDA-gated ion channels were investigated during the retinoic acid (RA) induced neuronal differentiation of NE-4C, a p53-deficient mouse neuroectodermal progenitor cell line. NR2A. NR2B, and NR2D subunit transcripts

Theoretical study on keto-enol tautomerisation of glutarimide for exploration of the isomerisation reaction pathway of glutamic acid in proteins using density functional theory

Science.gov (United States)

Fukuyoshi, Shuichi; Nakayoshi, Tomoki; Takahashi, Ohgi; Oda, Akifumi

2017-03-01

In order to elucidate the reason why glutamic acid residues have lesser racemisation reactivity than asparaginic acid, we investigated the racemisation energy barrier of piperidinedione, which is the presumed intermediate of the isomerisation reaction of L-Glu to D-Glu, by density functional theory calculations. In two-water-molecule-assisted racemisation, the activation barrier for keto-enol isomerisation was 28.1 kcal/mol. The result showed that the activation barrier for the racemisation of glutamic acid residues was not different from that for the racemisation of aspartic acid residues. Thus, glutamic acid residues can possibly cause the racemisation reaction if the cyclic intermediate stably exists.

The Blockade of Glutamate N-methyl-D-aspartate Receptors into the Prelimbic of Prefrontal Cortex Decreases Morphine-induced Conditioned Place Preference in Rat

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Samad Javadi

2017-12-01

Full Text Available BACKGROUND: The prelimbic area (PL of the prefrontal cortex is susceptible to abnormal developmental stimuli that raises the risk of addiction. Glutamate receptors play a key role in opiate reinforcement and reward functions in this area. Therefore, we examined the effect of the DL-2-amino-5-phosphonopentanoic acid (AP5, as N-methyl-D-aspartate (NMDA receptor antagonist into the PL on the phases of conditioned place preference (CPP induced by morphine. METHODS: Male Wistar rats were divided into 12 groups (3 surgical groups for each dose of morphine in any phase of CPP and anaesthetized with chloral hydrate. Cannula was implanted into the PL and the AP5 was injected into this area and morphine-induced CPP was investigated. Data were processed with the commercially available SPSS 22 software using one-way ANOVA and Tukey's test. p<0.05 were considered statistically significant. RESULTS: Our findings indicated, morphine in doses of 2.5 to 10 mg/kg induced CPP. Microinjection of various doses of the AP5 into the PL before the administration of the effective dose of morphine significantly reduced place preference in the acquisition and the expression phases of the CPP test compared to the sham group (p<0.001. In another set of our experiments was seen that, different doses of the AP5 with the ineffective dose of morphine only reduced the expression phase of the CPP (p<0.001 while, produced neither preference nor aversion effect on the acquisition phase (p=0.147. CONCLUSION: It seems that the glutamate NMDA receptors in the PL through memory formation and morphine-related reward signals play a critical role in addiction process during morphine-induced CPP. KEYWORDS: N-methyl-aspartate, morphine, glutamate receptor, prefrontal cortex, reward

Group I mGlu receptors potentiate synaptosomal [{sup 3}H]glutamate release independently of exogenously applied arachidonic acid

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Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J. [Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD (United Kingdom)

1999-04-01

In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [{sup 3}H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 {mu}M) increased 4AP-evoked [{sup 3}H]glutamate release (143.32{+-}2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC{sub 50}=1.60{+-}0.25 {mu}M; E{sub max}=147.61{+-}10.96% control) 4AP-evoked [{sup 3}H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu{sub 1} receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 {mu}M) and was BSA-insensitive. The selective mGlu{sub 5} receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300{mu}M) was without effect. DHPG (100 {mu}M) also potentiated both 30 mM and 50 mM K{sup +}-evoked [{sup 3}H]glutamate release (121.60{+-}12.77% and 121.50{+-}4.45% control, respectively). DHPG (100 {mu}M) failed to influence both 4AP-stimulated {sup 45}Ca{sup 2+} influx and 50 mM K{sup +}-induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A{sub 1} receptor, group II/III mGlu receptors or GABA{sub B} receptor activity is unlikely since 4AP-evoked [{sup 3}H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-{alpha}-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu{sub 1} receptor-like' receptor potentiates [{sup 3}H]glutamate release from cerebrocortical synaptosomes in the absence of

The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels

NARCIS (Netherlands)

Taati, Majid; Nayebzadeh, Hassan; Zendehdel, Morteza

This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series

Directory of Open Access Journals (Sweden)

Maurício Fernandes

2012-09-01

Full Text Available Neurological disorders associated with glutamic acid decarboxylase (GAD antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid

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Rinaldi, Tania; Kulangara, Karina; Antoniello, Katia

2007-01-01

as the commonly linked kinase calcium/calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes......Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain...

Activity of the lactate-alanine shuttle is independent of glutamate-glutamine cycle activity in cerebellar neuronal-astrocytic cultures

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Bak, Lasse K; Sickmann, Helle M; Schousboe, Arne

2004-01-01

The glutamate-glutamine cycle describes the neuronal release of glutamate into the synaptic cleft, astrocytic uptake, and conversion into glutamine, followed by release for use as a neuronal glutamate precursor. This only explains the fate of the carbon atoms, however, and not that of the ammonia....... Recently, a role for alanine has been proposed in transfer of ammonia between glutamatergic neurons and astrocytes, denoted the lactate-alanine shuttle (Waagepetersen et al. [ 2000] J. Neurochem. 75:471-479). The role of alanine in this context has been studied further using cerebellar neuronal cultures...... and corresponding neuronal-astrocytic cocultures. A superfusion paradigm was used to induce repetitively vesicular glutamate release by N-methyl-D-aspartate (NMDA) in the neurons, allowing the relative activity dependency of the lactate-alanine shuttle to be assessed. [(15)N]Alanine (0.2 mM), [2-(15)N]/[5-(15)N...

Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice.

Science.gov (United States)

Matsumura, N; Takeuchi, C; Hishikawa, K; Fujii, T; Nakaki, T

2001-05-18

Glufosinate ammonium, a broad-spectrum herbicide, causes convulsion in rodents and humans. Because of the structural similarities between glufosinate and glutamate, the convulsion induced by glufosinate ammonium may be ascribed to glutamate receptor activation. Three N-methyl-D-asparate (NMDA) receptor antagonists, dizocilpine, LY235959, and Compound 40, and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist, NBQX, were coadministrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the convulsions, while the AMPA/kainate receptor antagonist had no effect on the convulsion. These results suggest that the convulsion caused by glufosinate ammonium is mediated through NMDA receptors.

Cognitive decline in a patient with anti-glutamic acid decarboxylase autoimmunity; case report

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Takagi, Masahito; Yamasaki, Hiroshi; Endo, Keiko; Yamada, Tetsuya; Kaneko, Keizo; Oka, Yoshitomo; Mori, Etsuro

2011-01-01

Abstract Background Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for producing γ-aminobutyric acid, and it has been suggested that antibodies against GAD play a role in neurological conditions and type 1 diabetes. However, it is not known whether dementia appears as the sole neurological manifestation associated with anti-GAD antibodies in the central nervous system. Case presentation We describe the clinical, neuropsychological, and neuroradiological findings of a 73-year-ol...

A density functional and quantum Monte Carlo study of glutamic acid in vacuo and in a dielectric continuum medium

NARCIS (Netherlands)

Floris, F.; Filippi, Claudia; Amovilli, C.

2012-01-01

We present density functional theory (DFT) and quantum Monte Carlo (QMC) calculations of the glutamic acid and glutamate ion in vacuo and in various dielectric continuum media within the polarizable continuum model (PCM). In DFT, we employ the integral equation formalism variant of PCM while, in

The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions.

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Schmidt, André; Kometer, Michael; Bachmann, Rosilla; Seifritz, Erich; Vollenweider, Franz

2013-01-01

Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases. This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases. S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP. Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces. This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.

The glutamate/GABA-glutamine cycle

DEFF Research Database (Denmark)

Bak, Lasse K; Schousboe, Arne; Waagepetersen, Helle S

2006-01-01

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...... 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...

Activation of the Glutamic Acid-Dependent Acid Resistance System in Escherichia coli BL21(DE3) Leads to Increase of the Fatty Acid Biotransformation Activity.

Science.gov (United States)

Woo, Ji-Min; Kim, Ji-Won; Song, Ji-Won; Blank, Lars M; Park, Jin-Byung

The biosynthesis of carboxylic acids including fatty acids from biomass is central in envisaged biorefinery concepts. The productivities are often, however, low due to product toxicity that hamper whole-cell biocatalyst performance. Here, we have investigated factors that influence the tolerance of Escherichia coli to medium chain carboxylic acid (i.e., n-heptanoic acid)-induced stress. The metabolic and genomic responses of E. coli BL21(DE3) and MG1655 grown in the presence of n-heptanoic acid indicated that the GadA/B-based glutamic acid-dependent acid resistance (GDAR) system might be critical for cellular tolerance. The GDAR system, which is responsible for scavenging intracellular protons by catalyzing decarboxylation of glutamic acid, was inactive in E. coli BL21(DE3). Activation of the GDAR system in this strain by overexpressing the rcsB and dsrA genes, of which the gene products are involved in the activation of GadE and RpoS, respectively, resulted in acid tolerance not only to HCl but also to n-heptanoic acid. Furthermore, activation of the GDAR system allowed the recombinant E. coli BL21(DE3) expressing the alcohol dehydrogenase of Micrococcus luteus and the Baeyer-Villiger monooxygenase of Pseudomonas putida to reach 60% greater product concentration in the biotransformation of ricinoleic acid (i.e., 12-hydroxyoctadec-9-enoic acid (1)) into n-heptanoic acid (5) and 11-hydroxyundec-9-enoic acid (4). This study may contribute to engineering E. coli-based biocatalysts for the production of carboxylic acids from renewable biomass.

Activation of the Glutamic Acid-Dependent Acid Resistance System in Escherichia coli BL21(DE3 Leads to Increase of the Fatty Acid Biotransformation Activity.

Directory of Open Access Journals (Sweden)

Ji-Min Woo

Full Text Available The biosynthesis of carboxylic acids including fatty acids from biomass is central in envisaged biorefinery concepts. The productivities are often, however, low due to product toxicity that hamper whole-cell biocatalyst performance. Here, we have investigated factors that influence the tolerance of Escherichia coli to medium chain carboxylic acid (i.e., n-heptanoic acid-induced stress. The metabolic and genomic responses of E. coli BL21(DE3 and MG1655 grown in the presence of n-heptanoic acid indicated that the GadA/B-based glutamic acid-dependent acid resistance (GDAR system might be critical for cellular tolerance. The GDAR system, which is responsible for scavenging intracellular protons by catalyzing decarboxylation of glutamic acid, was inactive in E. coli BL21(DE3. Activation of the GDAR system in this strain by overexpressing the rcsB and dsrA genes, of which the gene products are involved in the activation of GadE and RpoS, respectively, resulted in acid tolerance not only to HCl but also to n-heptanoic acid. Furthermore, activation of the GDAR system allowed the recombinant E. coli BL21(DE3 expressing the alcohol dehydrogenase of Micrococcus luteus and the Baeyer-Villiger monooxygenase of Pseudomonas putida to reach 60% greater product concentration in the biotransformation of ricinoleic acid (i.e., 12-hydroxyoctadec-9-enoic acid (1 into n-heptanoic acid (5 and 11-hydroxyundec-9-enoic acid (4. This study may contribute to engineering E. coli-based biocatalysts for the production of carboxylic acids from renewable biomass.

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

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Hillhouse, T M; Negus, S S

2016-09-01

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1 mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK-801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists. © 2016 European Pain Federation - EFIC®

Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

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Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

2016-05-01

Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preservation of glutamic acid-iron chelate into montmorillonite to efficiently degrade Reactive Blue 19 in a Fenton system under sunlight irradiation at neutral pH

Science.gov (United States)

Huang, Zhujian; Wu, Pingxiao; Gong, Beini; Yang, Shanshan; Li, Hailing; Zhu, Ziao; Cui, Lihua

2016-05-01

To further enhance the visible light responsive property and the chemical stability of Fe/clay mineral catalysts, glutamic acid-iron chelate intercalated montmorillonite (G-Fe-Mt) was developed. The physiochemical properties of G-Fe-Mt were investigated by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), etc. The results showed that glutamic acid-iron chelates were successfully intercalated into the gallery of montmorillonite and the intercalated glutamic acid-iron chelate molecules were well preserved. The product G-Fe-Mt displayed excellent catalytic performance in heterogeneous photo-Fenton reaction under sunlight irradiation at acidic and neutral pH values. The chelation and the visible light responsiveness of glutamic acid produce a synergistic effect leading to greatly enhanced sunlight-Fenton reaction catalyzed by the heterogeneous G-Fe-Mt under neutral pH. G-Fe-Mt is a promising catalyst for advanced oxidation processes.

The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

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Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil); Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya [Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP (Brazil); Pessoa-Pureur, Regina, E-mail: rpureur@ufrgs.br [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil)

2014-04-01

Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to {sup 32}P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca{sup 2+}/calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca{sup 2+} quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca{sup 2+} influx through voltage-dependent Ca{sup 2+} channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative

Glutamate and GABA in schizophrenia

NARCIS (Netherlands)

Marsman, A.

2013-01-01

Schizophrenia is characterized by a loss of brain tissue, which may represent an ongoing pathophysiological process. Possible mechanisms that may be involved are the glutamatergic and GABAergic (gamma-aminobutyric acid) systems. Particularly hypofunction of the N-methyl-D-aspartate (NMDA) type of

Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

OpenAIRE

Khalil, Omari S; Pisar, Mazura; Forrest, Caroline M; Vincenten, Maria C J; Darlington, L Gail; Stone, Trevor W

2014-01-01

Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developme...

Expression and localization of ionotropic glutamate receptor subunits in the goldfish retina--an in situ hybridization and immunocytochemical study

NARCIS (Netherlands)

Vandenbranden, C. A.; Kamphuis, W.; Nunes Cardozo, B.; Kamermans, M.

2000-01-01

The expression and distribution of AMPA, kainate and NMDA glutamate receptor subunits was studied in the goldfish retina. For the immunocytochemical localization of the AMPA receptor antisera against GluR2, GluR2/3 and GluR4 were used, and for in situ hybridization rat specific probes for GluR1 and

Glutamate receptor agonists

DEFF Research Database (Denmark)

Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

2011-01-01

The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

4,4-Dimethyl- and diastereomeric 4-hydroxy-4-methyl-(2S)-glutamate analogues display distinct pharmacological profiles at ionotropic glutamate receptors and excitatory amino acid transporters

DEFF Research Database (Denmark)

Bunch, Lennart; Pickering, Darryl S; Gefflaut, Thierry

2009-01-01

this approach has provided important insight into the structure-activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4-disubstituted Glu analogues 1-3, which are hybrid structures......Subtype-selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4-substituted (S)-glutamate (Glu) analogues were synthesized, and altogether...

Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain.

Science.gov (United States)

Du, W; Aloyo, V J; Harvey, J A

1997-10-03

Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.

Rapid synthesis and metabolism of glutamate in N2-fixing bacteroids

International Nuclear Information System (INIS)

Salminen, S.O.; Streeter, J.G.

1987-01-01

Symbiotic nodule bacteroids are thought to support N 2 fixation mainly by metabolizing dicarboxylic acids to CO 2 , generating reductant and ATP required by nitrogenase. Bradyrhizobium japonicum bacteroids were isolated anaerobically and incubated at 2% O 2 with 14 C-labeled succinate, malate, glutamate, or aspartate. 14 CO 2 was collected, and the bacteroid contents separated into neutral, organic acid, and amino acid fractions. The respiration of substrates, relative to their uptake, was malate > glutamate > succinate > aspartate. Analysis of the fractions revealed that will all substrates the radioactivity was found mostly in the amino acid fraction. The labeling of the neutral fraction was negligible and only a small amount of label was found in the organic acid fraction indicating a small pool size. TLC of the amino acid fraction showed the label to be principally in glutamate. Glutamate contained 67, 80, 97, and 88% of the 14 C in the amino acid fraction in bacteroids fed with succinate, malate, glutamate and aspartate, respectively. The data suggest that glutamate may play an important role in the bacteroid function

H2O2 attenuates IGF-1R tyrosine phosphorylation and its survival signaling properties in neuronal cells via NR2B containing NMDA receptor.

Science.gov (United States)

Zeng, Zhiwen; Wang, Dejun; Gaur, Uma; Rifang, Liao; Wang, Haitao; Zheng, Wenhua

2017-09-12

Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H 2 O 2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H 2 O 2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H 2 O 2 , whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca 2+ influx contributes to the effects of H 2 O 2 . Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H 2 O 2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca 2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.

Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

Science.gov (United States)

Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

2016-08-01

Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

Task-specific enhancement of short-term, but not long-term, memory by class I metabotropic glutamate receptor antagonist 1-aminoindan-1,5-dicarboxylic acid in rats

DEFF Research Database (Denmark)

Christoffersen, G.R.J.; Christensen, Lone H.; Harrington, Nicholas R.

1999-01-01

Metabotropic glutamate receptors; Class I antagonist; 1-aminoindan-1,5-dicarboxylic acid; spatial learning; contextual conditioning; rats......Metabotropic glutamate receptors; Class I antagonist; 1-aminoindan-1,5-dicarboxylic acid; spatial learning; contextual conditioning; rats...

The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear.

Science.gov (United States)

Handford, Charlotte E; Tan, Shawn; Lawrence, Andrew J; Kim, Jee Hyun

2014-09-01

The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.

Glutamate receptor ligands

DEFF Research Database (Denmark)

Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

2002-01-01

Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

PYROLYTIC PRODUCTS FROM TRYPTOPHAN AND GLUTAMIC-ACID ARE POSITIVE IN THE MAMMALIAN SPOT-TEST

DEFF Research Database (Denmark)

Jensen, Niels Juul

1983-01-01

Pyrolysates of tryptophan (Trp-P-2) and glutamic acid (Glu-P-1) are known mutagens in in vitro short term mutagenicity tests, and have also shown carcinogenic effects in long term animal studies. The present study demonstrates that they also produce mutations in somatic cells. This result...

Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

Institute of Scientific and Technical Information of China (English)

Vicente Felipo

2006-01-01

Patients with liver disease may present hepatic encephalopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations,including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death.The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE.These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced,which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE.However, it is necessary to previously assess the possible secondary effects.Patients with HE may present psychomotor slowing,hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs.

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Kaszaki, J; Palásthy, Z; Erczes, D; Rácz, A; Torday, C; Varga, G; Vécsei, L; Boros, M

2008-01-01

Kynurenic acid (KynA), an endogenous antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, protects the central nervous system in excitotoxic neurological diseases. We hypothesized that the inhibition of enteric glutamate receptors by KynA may influence dysmotility in the gastrointestinal tract. Group 1 of healthy dogs served as the sham-operated control, in group 2, the animals were treated with KynA, while in groups 3 and 4 mechanical colon obstruction was maintained for 7 h. Group 4 was treated with KynA at the onset of ileus. Hemodynamics and motility changes were monitored, and the activities of xanthine oxidoreductase (XOR) and myeloperoxidase (MPO) were determined from tissue samples. Colon obstruction induced a hyperdynamic circulatory reaction, significantly elevated the motility index and increased the mucosal leucocyte accumulation and the XOR activity. The KynA treatment augmented the tone of the colon, permanently decreased the motility index of the giant colonic contractions and reduced the increases in XOR and MPO activities. These effects were concomitant with the in vitro inhibition of XOR activity. In conclusion, KynA antagonizes the obstruction-induced motility responses and XOR activation in the colon. Inhibition of enteric NMDA receptors may provide an option to influence intestinal hypermotility and inflammatory changes.

Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

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Laurent Ladepeche

Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

Biogenic glutamic acid-based resin: Its synthesis and application in the removal of cobalt(II)

International Nuclear Information System (INIS)

Jamiu, Zakariyah A.; Saleh, Tawfik A.; Ali, Shaikh A.

2017-01-01

Highlights: • A novel resin embedded with metal chelating glutamic acid was synthesized. • The biogenic amino acid residues imparted remarkable efficacy to remove Co(II). • The resin showed excellent ability to remove various metals from wastewater. - Abstract: Inexpensive biogenic glutamic acid has been utilized to synthesize a cross-linked dianionic polyelectrolyte (CDAP) containing metal chelating ligands. Cycloterpolymerization, using azoisobutyronitrile as an initiator, of N,N-diallylglutamic acid hydrochloride, sulfur dioxide and a cross-linker afforded a pH-responsive cross-linked polyzwitterionic acid (CPZA) which upon basification with NaOH was converted into CDAP. The new resin, characterized by a multitude of spectroscopic techniques as well as Scanning Electron Microscopy (SEM) and Brunauer–Emmett–Teller (BET) analyses, was evaluated for the removal of Co(II) as a model case under different conditions. The adsorption capacity of 137 mg g"−"1 does indeed make the resin as one of the most effective sorbents in recent times. The resin leverages its cheap natural source and ease of regeneration in combination with its high and fast uptake capacities to offer a great promise for wastewater treatment. The resin has demonstrated remarkable efficiency in removing toxic metal ions including arsenic from a wastewater sample.

Biogenic glutamic acid-based resin: Its synthesis and application in the removal of cobalt(II)

Energy Technology Data Exchange (ETDEWEB)

Jamiu, Zakariyah A.; Saleh, Tawfik A.; Ali, Shaikh A., E-mail: shaikh@kfupm.edu.sa

2017-04-05

Highlights: • A novel resin embedded with metal chelating glutamic acid was synthesized. • The biogenic amino acid residues imparted remarkable efficacy to remove Co(II). • The resin showed excellent ability to remove various metals from wastewater. - Abstract: Inexpensive biogenic glutamic acid has been utilized to synthesize a cross-linked dianionic polyelectrolyte (CDAP) containing metal chelating ligands. Cycloterpolymerization, using azoisobutyronitrile as an initiator, of N,N-diallylglutamic acid hydrochloride, sulfur dioxide and a cross-linker afforded a pH-responsive cross-linked polyzwitterionic acid (CPZA) which upon basification with NaOH was converted into CDAP. The new resin, characterized by a multitude of spectroscopic techniques as well as Scanning Electron Microscopy (SEM) and Brunauer–Emmett–Teller (BET) analyses, was evaluated for the removal of Co(II) as a model case under different conditions. The adsorption capacity of 137 mg g{sup −1} does indeed make the resin as one of the most effective sorbents in recent times. The resin leverages its cheap natural source and ease of regeneration in combination with its high and fast uptake capacities to offer a great promise for wastewater treatment. The resin has demonstrated remarkable efficiency in removing toxic metal ions including arsenic from a wastewater sample.

Effect of glucose on poly-γ-glutamic acid metabolism in Bacillus licheniformis.

Science.gov (United States)

Yu, Wencheng; Chen, Zhen; Ye, Hong; Liu, Peize; Li, Zhipeng; Wang, Yuanpeng; Li, Qingbiao; Yan, Shan; Zhong, Chuan-Jian; He, Ning

2017-02-08

Poly-gamma-glutamic acid (γ-PGA) is a promising macromolecule with potential as a replacement for chemosynthetic polymers. γ-PGA can be produced by many microorganisms, including Bacillus species. Bacillus licheniformis CGMCC2876 secretes γ-PGA when using glycerol and trisodium citrate as its optimal carbon sources and secretes polysaccharides when using glucose as the sole carbon source. To better understand the metabolic mechanism underlying the secretion of polymeric substances, SWATH was applied to investigate the effect of glucose on the production of polysaccharides and γ-PGA at the proteome level. The addition of glucose at 5 or 10 g/L of glucose decreased the γ-PGA concentration by 31.54 or 61.62%, respectively, whereas the polysaccharide concentration increased from 5.2 to 43.47%. Several proteins playing related roles in γ-PGA and polysaccharide synthesis were identified using the SWATH acquisition LC-MS/MS method. CcpA and CcpN co-enhanced glycolysis and suppressed carbon flux into the TCA cycle, consequently slowing glutamic acid synthesis. On the other hand, CcpN cut off the carbon flux from glycerol metabolism and further reduced γ-PGA production. CcpA activated a series of operons (glm and epsA-O) to reallocate the carbon flux to polysaccharide synthesis when glucose was present. The production of γ-PGA was influenced by NrgB, which converted the major nitrogen metabolic flux between NH 4 + and glutamate. The mechanism by which B. licheniformis regulates two macromolecules was proposed for the first time in this paper. This genetic information will facilitate the engineering of bacteria for practicable strategies for the fermentation of γ-PGA and polysaccharides for diverse applications.

Glutamic Acid Signal Synchronizes Protein Synthesis Kinetics in Hepatocytes from Old Rats for the Following Several Days. Cell Metabolism Memory.

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Brodsky, V Y; Malchenko, L A; Lazarev, D S; Butorina, N N; Dubovaya, T K; Zvezdina, N D

2018-03-01

The kinetics of protein synthesis was investigated in primary cultures of hepatocytes from old rats in serum-free medium. The rats were fed mixed fodder supplemented with glutamic acid and then transferred to a regular mixed fodder. The amplitude of protein synthesis rhythm in hepatocytes isolated from these rats increased on average 2-fold in comparison with the rats not receiving glutamic acid supplement. Based on this indicator reflecting the degree of cell-cell interactions, the cells from old rats were not different from those of young rats. The effect was preserved for 3-4 days. These results are discussed in connection with our previous data on preservation of the effect of single administration of gangliosides, noradrenaline, serotonin, and other synchronizers on various cell populations. In contrast to the other investigated factors, glutamic acid is capable of penetrating the blood-brain barrier, which makes its effect possible not only in the case of hepatocytes and other non-brain cells, but also in neurons.

Kinetics of reactions of aquacobalamin with aspartic and glutamic acids and their amides in water solutions

Science.gov (United States)

Bui, T. T. T.; Sal'nikov, D. S.; Dereven'kov, I. A.; Makarov, S. V.

2017-04-01

The kinetics of aquacobalamin reaction with aspartic and glutamic acids, and with their amides in water solutions, is studied via spectrophotometry. The kinetic and activation parameters of the process are determined. It is shown that the reaction product is cobalamin-amino acid complex. The data are compared to results on the reaction between aquacobalamin and primary amines.

Increased NMDA and AMPA receptor densities in the anterior cingulate cortex in schizophrenia

International Nuclear Information System (INIS)

Zavitsanou, K.; Huang, X.-F.

2002-01-01

Full text: The anterior cingulate cortex (ACC) is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Since a disturbed balance between excitatory and inhibitory activity is suggested to occur in the ACC in schizophrenia, the present study has focused on the analysis of binding of [ 3 H]MK801, [ 3 H]AMPA and [ 3 H]kainate, radioligands which respectively label the NMDA, AMPA and kainate receptors of the ionotropic glutamate receptor family in the ACC of 10 schizophrenia patients and 10 matched controls, using quantitative autoradiography. AMPA receptor densities were higher in cortical layer II whereas NMDA receptor densities were higher in cortical layers II-III in the ACC of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [ 3 H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared to the control group. Similarly, a significant 17% increase of [ 3 H]MK801 binding was observed in layers II-III in the schizophrenia group. No statistically significant differences were observed for [ 3 H] kainate binding between the two groups. These results suggest that ionotropic glutamate receptors are differentially altered in the ACC of schizophrenia. The increase in [ 3 H]AMPA and [ 3 H]MK801 binding points to a postsynaptic compensation for impaired glutamatergic neurotransmission in the ACC in schizophrenia. Such abnormality could lead to an imbalance between the excitatory and inhibitory neurotransmission in this brain area that may contribute to the emergence of some schizophrenia symptoms. Copyright (2002) Australian Neuroscience Society

Improved production of poly-γ-glutamic acid by Bacillus subtilis D7 isolated from Doenjang, a Korean traditional fermented food, and its antioxidant activity.

Science.gov (United States)

Lee, Na-Ri; Lee, Sang-Mee; Cho, Kwang-Sik; Jeong, Seong-Yun; Hwang, Dae-Youn; Kim, Dong-Seob; Hong, Chang-Oh; Son, Hong-Joo

2014-06-01

The objectives of this study was to improve poly-γ-glutamic acid (γ-PGA) production by Bacillus subtilis D7 isolated from a Korean traditional fermented food and to assess its antioxidant activity for applications in the cosmetics and pharmaceutical industries. Strain D7 produced γ-PGA in the absence of L-glutamic acid, indicating L-glutamic acid-independent production. However, the addition of L-glutamic acid increased γ-PGA production. Several tricarboxylic acid cycle intermediates and amino acids could serve as the metabolic precursors for γ-PGA production, and the addition of pyruvic acid and D-glutamic acid to culture medium improved the yield of γ-PGA markedly. The maximum yield of γ-PGA obtained was 24.93 ± 0.64 g/l in improved medium, which was about 5.4-fold higher than the yield obtained in basal medium. γ-PGA was found to have 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (46.8 ± 1.5 %), hydroxyl radical scavenging activity (52.0 ± 1.8 %), 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonate (ABTS) radical scavenging activity (42.1 ± 1.8 %), nitric oxide scavenging activity (35.1 ± 1.3 %), reducing power (0.304 ± 0.008), and metal chelating activity (91.3 ± 3.5 %). These results indicate that γ-PGA has a potential use in the food, cosmetics, and biomedical industries for the development of novel products with radical scavenging activity. As far as we are aware, this is the first report to describe the antioxidant activityof γ-PGA produced by bacteria.

Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

Science.gov (United States)

McKay, Sean; Bengtson, C. Peter; Bading, Hilmar; Wyllie, David J.A.; Hardingham, Giles E.

2013-01-01

MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation. This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’. PMID:23402996

Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.

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Carolin Wippel

Full Text Available Streptococcus pneumoniae (pneumococcal meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

Estudio computacional de las relaciones evolutivas de los receptores ionotrópicos NMDA, AMPA y kainato en cuatro especies de primates

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Francy Johanna Moreno-Pedraza

2010-12-01

Full Text Available Computational study of the evolutionary relationships of the ionotropic receptors NMDA, AMPA and kainate in four species ofprimates. Objective. To identify the influence of changes on the secondary structure and evolutionary relationship of NMDA, AMPA andkainate receptors in Homo sapiens, Pan troglodytes, Pongo pygmaeus and Macaca mulatta. Materials and methods. We identified 91sequences for NMDA, AMPA and kainate receptors and analyzed with software for predicting secondary structure, phosphorylation sites,multiple alignments, selection of protein evolution models and phylogenetic prediction. Results. We found that subunits GLUR5, NR2A,NR2C and NR3A showed structural changes in the C-terminal region and formation or loss of phosphorylation sites in this zone.Additionally the phylogenetic prediction suggests that the NMDA NR2 subunits are the closest to the ancestral node that gives rise to theother subunits. Conclusions. Changes in structure and phosphorylation sites in GLUR5, NR2A, NR2C and NR3A subunits suggestvariations in the interaction of the C-terminal region with kinase proteins and with proteins with PDZ domains, which could affect thetrafficking and anchoring of the subunits. On the other hand, the phylogenetic prediction suggests that the changes that occurred in the NR2subunits gave rise to the other subunits of glutamate ionotropic receptors, primarily because the NMDA and particularly the NR2D subunitsare the most closely related to the ancestral node that possibly gave rise to the iGluRs.

Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

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Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

2016-11-01

Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits

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Liu, Xiao; Li, Jitao; Guo, Chunmei; Wang, Hongli; Sun, Yaxin; Wang, Han; Su, Yun-Ai; Li, Keqing; Si, Tianmei

2018-01-01

Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine. PMID:29375333

A new technique for measuring protein turnover in the gut, liver and kidneys of lean and obese mice with [3H] glutamic acid

International Nuclear Information System (INIS)

Miller, B.G.; Grimble, R.F.; Taylor, T.G.

1978-01-01

Measurements have been made of the incorporation of an intraperitoneal injection of [ 3 H]glutamate into the protein of the gut, liver and kidney of lean and obese siblings of the genetically obese mouse. Recycling of the 3 H was minimized by using glutamate labelled at the C-2 position. Loss of label from the amino acid pool by transamination and deamination was rapid, with a half-life of 4 h. In tissue protein the amino acid showing the highest 3 H radioactivity was glutamate. The half-lives for protein synthesis and catabolism were calculated from the decay curves of both specific and total radioactivity of [ 3 H] glutamate in tissue protein. No significant differences were found between kidney, liver and gut in lean and obese mice. (author)

Displacement of DL-[3H]-2-amino-4-phosphonobutanoic acid ( [3H]APB) binding with methyl-substituted APB analogues and glutamate agonists

International Nuclear Information System (INIS)

Robinson, M.B.; Crooks, S.L.; Johnson, R.L.; Koerner, J.F.

1985-01-01

The binding of the excitatory amino acid antagonist DL-2-amino-4-phosphonobutanoic acid (DL-APB) to rat brain synaptic plasma membranes was characterized. As determined by Scatchard analysis, the binding was saturable and homogeneous with a Kd = 6.0 microM and Bmax = 380 pmol/mg of protein. The binding was dependent on the presence of Ca 2+ and Cl - ions and was diminished upon freezing. The association rate constant was 6.8 X 10(-3) microM -1 min -1 , and the dissociation rate constant was 2.0 X 10(-2) min -1 . The L isomers of APB, glutamate, and aspartate were more potent as displacers of APB binding than the D isomers. With the exception of kynurenic acid, all compounds examined in both systems were more potent as displacers of APB binding than as inhibitors of synaptic transmission. This difference in potency was most pronounced for agonists at dentate granule cells. L-Glutamate, D-glutamate, and L-glutamate tetrazole were between 140- and 7500-fold more potent as displacers of DL-APB binding than as inhibitors of synaptic transmission. D-2-Amino-5-phosphonopentanoic acid and alpha-methyl-APB were between 10- and 20-fold more potent as displacers of binding

Chemical protection against radiation effects on Serum transaminase and the levels of glutamic and pyruvic acids following gamma irradiation of rats

International Nuclear Information System (INIS)

Mahdy, A.M.; EL-Kashef, H.S.

1988-01-01

The present study been carried out to evaluate the radioprotective efficiency of urea and vitamin E for protecting certain enzymatic systems from deleterious radiation effects. The activities of serum transaminase; aspartate aminotransferase (A S T) and alanine aminotransferase (A L T); as well as their relative substrates; glutamic and pyruvic acid levels; were selected for this study. The results indicated that whole body gamma irradiation at the dose of 7 Gy caused an evident elevation in the activities of both A S T and A L T and in the level of pyruvic acid at the experiment period (first,third,seventh and tenth days post irradiation). On the other hand the free glutamic acid level decreased at all post irradiation days. The variation in both enzymatic activities, pyruvic and glutamic acid levels became less pronounced in rats treated with either urea or vitamin E as chemical radioprotectors before whole body gamma irradiation. The results showed that the two agents are good radioprotectors, with respect to these parameters under investigation

Synthesis and evaluation of a glutamic acid-modified hPAMAM complex as a promising versatile gene carrier.

Science.gov (United States)

Hemmati, Mohammad; Kazemi, Bahram; Najafi, Farhood; Zarebkohan, Amir; Shirkoohi, Reza

2016-01-01

Hyperbranched poly(amidoamine) (HPAMAM), structurally analogous to polyamidoamine dendrimer (PAMAM) dendrimers, has been suggested to be an effective carrier for gene delivery. In the present study, glutamic acid-modified hPAMAM was developed as a novel non-viral gene carrier for the first time. The hPAMAM was synthesized by using a modified one-pot method. DNA was found to be bound to hPAMAM at different weight ratios (WhPAMAM/WDNA). The resulting HPAMAM-Glu20 was able to efficiently protect the encapsulated-DNA against degradation for over 2 h. In addition to low cytotoxicity, the transfection efficiency of hPAMAM-Glu20 represented much higher (p glutamic amino acid (Glu)-based gene delivery is an economical, effective and biocompatible method.

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

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Nuno A. L. Pereira

2016-08-01

Full Text Available Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool, and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i a stereoselective cyclocondensation of (S- or (R-tryptophanol with appropriate racemic δ-oxoesters; (ii a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease. This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

Effects of poly-γ-glutamic acid biopreparation (PGAB) on nitrogen conservation in the coastal saline soil

Science.gov (United States)

Chen, Lihua; Xu, Xianghong; Zhang, Huan; Han, Rui; Cheng, Yao; Tan, Xueyi; Chen, Xuanyu

2017-04-01

Water leaching is the major method to decrease soil salinity of the coastal saline soil. Conservation of soil nutrition in the soil ameliorating process is helpful to maintain soil fertility and prevent environment pollution. In the experiment, glutamic acid and poly-γ-glutamic acid (PGA) producing bacteria were isolated for manufacturing the PGA biopreparation (PGAB), and the effect of PGAB on the soil nitrogen (N) conservation was assayed. The glutamic acid and PGA producing bacteria were identified as Brevibacterium flavum and Bacillus amyloliquefaciens. After soil leached with water for 90 days, compared to control treatment, salt concentration of 0-30cm soil with PGAB treatment was lowered by 39.93%, however the total N loss was decreased by 65.37%. Compared to control, the microbial biomass N increased by 1.19 times at 0-30 cm soil with PGAB treatment. The populations of soil total bacteria, fungi, actinomyces, nitrogen fixing bacteria, ammonifying bacteria, nitrifying bacteria and denitrifying bacteria and biomass of soil algae were significantly increased in PGAB treatment, while anaerobic bacteria decreased (P 0.25 mm and 0.02 mm < diameter <0.25 mm were increased by 2.93 times and 26.79% respectively in PGAB treatment. The soil erosion-resistance coefficient of PGAB treatment increased by 50%. All these suggested that the PGAB conserved the soil nitrogen effectively in the process of soil water leaching and improved the coastal saline soil quality.

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

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Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures.

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Meloni, Bruno P; Craig, Amanda J; Milech, Nadia; Hopkins, Richard M; Watt, Paul M; Knuckey, Neville W

2014-03-01

Cell-penetrating peptides (CPPs) are small peptides (typically 5-25 amino acids), which are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids, or drugs into cells. However, several recent studies have demonstrated that the TAT CPP has neuroprotective properties. Therefore, in this study, we assessed the TAT and three other CPPs (penetratin, Arg-9, Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose deprivation). Arg-9, penetratin, and TAT-D displayed consistent and high level neuroprotective activity in both the glutamic acid (IC50: 0.78, 3.4, 13.9 μM) and kainic acid (IC50: 0.81, 2.0, 6.2 μM) injury models, while Pep-1 was ineffective. The TAT-D isoform displayed similar efficacy to the TAT-L isoform in the glutamic acid model. Interestingly, Arg-9 was the only CPP that displayed efficacy when washed-out prior to glutamic acid exposure. Neuroprotection following in vitro ischemia was more variable with all peptides providing some level of neuroprotection (IC50; Arg-9: 6.0 μM, TAT-D: 7.1 μM, penetratin/Pep-1: >10 μM). The positive control peptides JNKI-1D-TAT (JNK inhibitory peptide) and/or PYC36L-TAT (AP-1 inhibitory peptide) were neuroprotective in all models. Finally, in a post-glutamic acid treatment experiment, Arg-9 was highly effective when added immediately after, and mildly effective when added 15 min post-insult, while the JNKI-1D-TAT control peptide was ineffective when added post-insult. These findings demonstrate that different CPPs have the ability to inhibit neurodamaging events/pathways associated with excitotoxic and ischemic injuries. More importantly, they highlight the need to interpret neuroprotection studies when using CPPs as delivery agents with caution. On a positive note, the cytoprotective properties of CPPs suggests they are ideal carrier molecules to

Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

Science.gov (United States)

Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

Studies of the radioprotective properties of nicotinyl compounds, aspartic acid, glutamic acid and methionine

International Nuclear Information System (INIS)

Itzel-Kietzmann, V.M.

1986-01-01

Radioprotective properties of sodium salts of nicotinyl aspartic acid, nicotinyl methionyl aspartic acid and nicotinyl glutamic acid were tested in mice (NMRI). Experimental animals were irradiated by rayage (9,5 Gy). Parameters were: survival rate, peritoneal fluid cell count, weight and DNA concentration of spleen, hepatic DNA polymerase activity and rate of protein synthesis, lactate dehydrogenase activity in serum, maltase, sucrase and leucine aminopeptidase activitiy in duodenum and jejunum. Following results were obtained: 1. There was no significant difference in survival rate of treated and untreated animals. In treated animals only a short prolongation of survival time was observed. 2. After irradiation a quick reduction of splenic weight and DNA concentration was measured. 3. A reduction of DNA polymerase activity in liver was observed in treated and untreated mice. The rate of hepatic protein synthesis was similar in all animals. A final decrease was observed. 4. Variable activities of maltase, sucrase and leucine aminopeptidase activity in duodenum and jejunum indicated no radioprotective effect of tested substances. In conclusion of these results the tested substances show no significant radioprotective properties. (orig.) [de

Combretastatin A4/poly(L-glutamic acid-graft-PEG conjugates self-assembled to nanoparticles

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Yang Ou

2018-03-01

Full Text Available Combretastatin A4 (CA4 possesses varying ability to cause vascular disruption in tumors, while the short half-life, low water solubility and deactivation of many CA4 analogs during storage limited its antitumor efficacy and drug stability. A novel macromolecular conjugate of CA4 (CA4-PL was synthesized by covalent bonding of CA4 onto poly(L-glutamic acid-graft-polyethylene glycol (PLG-g-PEG via Yamaguchi reaction. The obtained CA4-PL was characterized by 1H NMR, GPC, and UV methods, and the properties of the nanoparticles composed of CA4-PL, including critical aggregation concentration, size and size distribution, and morphology, were investigated. CA4-PL can self-assemble to form micelle-like nanoparticles of 80~120 nm in diameter, which may have potential to improve the blood circulation period as well as the targetability of CA4, and find applications to treat various tumors when combined with traditional chemotherapy or radio therapy. Keywords: Combretastatin A4, Macromolecular conjugate, Poly(L-glutamic acid-graft-polyethylene glycol, Self-assemble, Nanoparticles

Preservation of glutamic acid-iron chelate into montmorillonite to efficiently degrade Reactive Blue 19 in a Fenton system under sunlight irradiation at neutral pH

Energy Technology Data Exchange (ETDEWEB)

Huang, Zhujian [College of Natural Resources and Environment, South China Agricultural University, Guangzhou 510642 (China); Wu, Pingxiao, E-mail: pppxwu@scut.edu.cn [School of Environment and Energy, South China University of Technology, Guangzhou Higher Education Mega Centre, Guangzhou 510006 (China); The Key Lab of Pollution Control and Ecosystem Restoration in Industry Clusters, Ministry of Education, Guangzhou 510006 (China); Gong, Beini; Yang, Shanshan; Li, Hailing [School of Environment and Energy, South China University of Technology, Guangzhou Higher Education Mega Centre, Guangzhou 510006 (China); Zhu, Ziao; Cui, Lihua [College of Natural Resources and Environment, South China Agricultural University, Guangzhou 510642 (China)

2016-05-01

Graphical abstract: - Highlights: • G–Fe chelate molecules were well preserved into montmorillonite. • The product shows an excellent catalytic activity under sunlight at neutral pH value. • G–Fe–Mt is a promising catalyst for advanced oxidation processes. - Abstract: To further enhance the visible light responsive property and the chemical stability of Fe/clay mineral catalysts, glutamic acid-iron chelate intercalated montmorillonite (G–Fe–Mt) was developed. The physiochemical properties of G–Fe–Mt were investigated by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV–vis diffuse reflectance spectroscopy (DRS), etc. The results showed that glutamic acid-iron chelates were successfully intercalated into the gallery of montmorillonite and the intercalated glutamic acid-iron chelate molecules were well preserved. The product G–Fe–Mt displayed excellent catalytic performance in heterogeneous photo-Fenton reaction under sunlight irradiation at acidic and neutral pH values. The chelation and the visible light responsiveness of glutamic acid produce a synergistic effect leading to greatly enhanced sunlight-Fenton reaction catalyzed by the heterogeneous G–Fe–Mt under neutral pH. G–Fe–Mt is a promising catalyst for advanced oxidation processes.

Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment.

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Lucio A Ramos-Chávez

2015-02-01

Full Text Available Inorganic arsenic (iAs is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH, which is the main antioxidant in the central nervous system. In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females.

Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease.

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Calon, Frédéric; Lim, Giselle P; Morihara, Takashi; Yang, Fusheng; Ubeda, Oliver; Salem, Norman; Frautschy, Sally A; Cole, Greg M

2005-08-01

Epidemiological data indicate that low n-3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n-3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil-induced n-3 PFA deficiency caused a decrease in N-methyl-D-aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal-associated protein 25 (SNAP-25). n-3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca2+/calmodulin-dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n-3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85alpha phosphatidylinositol 3-kinase levels. Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n-3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n-3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n-3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.

Disruption of pknG enhances production of gamma-aminobutyric acid by Corynebacterium glutamicum expressing glutamate decarboxylase.

Science.gov (United States)

Okai, Naoko; Takahashi, Chihiro; Hatada, Kazuki; Ogino, Chiaki; Kondo, Akihiko

2014-01-01

Gamma-aminobutyric acid (GABA), a building block of the biodegradable plastic polyamide 4, is synthesized from glucose by Corynebacterium glutamicum that expresses Escherichia coli glutamate decarboxylase (GAD) B encoded by gadB. This strain was engineered to produce GABA more efficiently from biomass-derived sugars. To enhance GABA production further by increasing the intracellular concentration of its precursor glutamate, we focused on engineering pknG (encoding serine/threonine protein kinase G), which controls the activity of 2-oxoglutarate dehydrogenase (Odh) in the tricarboxylic acid cycle branch point leading to glutamate synthesis. We succeeded in expressing GadB in a C. glutamicum strain harboring a deletion of pknG. C. glutamicum strains GAD and GAD ∆pknG were cultured in GP2 medium containing 100 g L(-1) glucose and 0.1 mM pyridoxal 5'-phosphate. Strain GAD∆pknG produced 31.1 ± 0.41 g L(-1) (0.259 g L(-1) h(-1)) of GABA in 120 hours, representing a 2.29-fold higher level compared with GAD. The production yield of GABA from glucose by GAD∆pknG reached 0.893 mol mol(-1).

Controversial Effects of D-Amino Acid Oxidase Activator (DAOA)/G72 on D-Amino Acid Oxidase (DAO) Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA) Receptor Hypofunction Point of View.

Science.gov (United States)

Jagannath, Vinita; Brotzakis, Zacharias Faidon; Parrinello, Michele; Walitza, Susanne; Grünblatt, Edna

2017-01-01

Dysfunction of D-amino acid oxidase ( DAO ) and DAO activator ( DAOA )/ G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA) receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y), astrocyte-like (1321N1) and kidney-like (HEK293) human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO) showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD)] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD), which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated.

Controversial Effects of D-Amino Acid Oxidase Activator (DAOA/G72 on D-Amino Acid Oxidase (DAO Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA Receptor Hypofunction Point of View

Directory of Open Access Journals (Sweden)

Vinita Jagannath

2017-10-01

Full Text Available Dysfunction of D-amino acid oxidase (DAO and DAO activator (DAOA/G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y, astrocyte-like (1321N1 and kidney-like (HEK293 human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD, which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated.

Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

Energy Technology Data Exchange (ETDEWEB)

Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. (College de France, Paris (France))

1991-05-01

Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.

The Effect of MSG (Monosodium Glutamate Addition on The Quality of Yoghurt Frozen Culture Starter Viewed Viability, pH Value and Acidity

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Aris Sri Widati

2012-02-01

Full Text Available The objective of this study was to investigate wether the effect of percentage monosodium glutamat addition on the quality of yoghurt frozen culture starter viewed viability, pH value and acidity.The experimental design used in this study was Randomised Complete Design and the treatment were four levels of monosodium glutamate concentration respectively 0% (without monosodium glutamat 10%, 15% and 20% from medium. Each treatment were three times replicated. The research result showed that the difference of monosodium glutamate concentration  did not gave a significant effect (P>0.05 on viability of yoghurt frozen culture starter and acidity of yoghurt made by frozen culture starter but it gave a significant effect (P<0.05 on pH value. It can be concluded that different monosodium glutamate concentration had a different quality on frozen culture starter yoghurt. The addition of monosodium glutamate up to 20% necessarily indicate increase on quality of yoghurt frozen culture starter. Keywords: culture starter yoghurt, freezing, cryoprotectant

Glutamate Efflux at the Blood-Brain Barrier

DEFF Research Database (Denmark)

Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

2014-01-01

is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high...... affinity concentrative uptake of L-glutamate from the brain interstitial fluid into the capillary endothelial cells. The mechanisms in between L-glutamate uptake in the endothelial cells and L-glutamate appearing in the blood are still unclear and may involve a luminal transporter for L......-glutamate, metabolism of L-glutamate and transport of metabolites or a combination of the two. However, both in vitro and in vivo studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. This review summarizes the current knowledge on the brain-to-blood L-glutamate efflux...

Glutamine and glutamate as vital metabolites

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Newsholme P.

2003-01-01

Full Text Available Glucose is widely accepted as the primary nutrient for the maintenance and promotion of cell function. This metabolite leads to production of ATP, NADPH and precursors for the synthesis of macromolecules such as nucleic acids and phospholipids. We propose that, in addition to glucose, the 5-carbon amino acids glutamine and glutamate should be considered to be equally important for maintenance and promotion of cell function. The functions of glutamine/glutamate are many, i.e., they are substrates for protein synthesis, anabolic precursors for muscle growth, they regulate acid-base balance in the kidney, they are substrates for ureagenesis in the liver and for hepatic and renal gluconeogenesis, they act as an oxidative fuel for the intestine and cells of the immune system, provide inter-organ nitrogen transport, and act as precursors of neurotransmitter synthesis, of nucleotide and nucleic acid synthesis and of glutathione production. Many of these functions are interrelated with glucose metabolism. The specialized aspects of glutamine/glutamate metabolism of different glutamine-utilizing cells are discussed in the context of glucose requirements and cell function.

Expression of the human isoform of glutamate dehydrogenase, hGDH2, augments TCA cycle capacity and oxidative metabolism of glutamate during glucose deprivation in astrocytes

DEFF Research Database (Denmark)

Nissen, Jakob D; Lykke, Kasper; Bryk, Jaroslaw

2017-01-01

A key enzyme in brain glutamate homeostasis is glutamate dehydrogenase (GDH) which links carbohydrate and amino acid metabolism mediating glutamate degradation to CO2 and expanding tricarboxylic acid (TCA) cycle capacity with intermediates, i.e. anaplerosis. Humans express two GDH isoforms, GDH1...... and 2, whereas most other mammals express only GDH1. hGDH1 is widely expressed in human brain while hGDH2 is confined to astrocytes. The two isoforms display different enzymatic properties and the nature of these supports that hGDH2 expression in astrocytes potentially increases glutamate oxidation...

Dietary supplementation with arginine and glutamic acid modifies growth performance, carcass traits, and meat quality in growing-finishing pigs.

Science.gov (United States)

Hu, C J; Jiang, Q Y; Zhang, T; Yin, Y L; Li, F N; Deng, J P; Wu, G Y; Kong, X F

2017-06-01

Sixty Duroc × Large White × Landrace pigs with an average initial BW of 77.1 ± 1.3 kg were used to investigate the effects of dietary supplementation with arginine and glutamic acid on growth performance, carcass traits, and meat quality in growing-finishing pigs. The animals were randomly assigned to 1 of 5 treatment groups (12 pigs/group, male:female ratio 1:1). The pigs in the control group were fed a basal diet (basal diet group), and those in the experimental groups were fed the basal diet supplemented with 2.05% -alanine (isonitrogenous group), 1.0% -arginine (Arg group), 1% glutamic acid + 1.44% -alanine (Glu group), or 1.0% -arginine + 1.0% glutamic acid (Arg+Glu group). After a 60-d period of supplementation, growth performance, carcass traits, and meat quality were evaluated. The results showed no significant differences ( > 0.05) in growth performance and carcass traits of the pigs in the Arg group relative to the basal diet group; however, the longissimus dorsi (LD) muscle and back fat showed a decrease ( 0.05) on the final BW, phase 2 ADFI, and average daily weight gain in pigs but decreased ( acid composition without affecting growth performance and s.c. fat in pigs, providing a novel strategy to enhance meat quality in growing-finishing pigs.

L-Aspartic and l-glutamic acid ester-based ProTides of anticancer nucleosides: Synthesis and antitumoral evaluation.

Science.gov (United States)

Gao, Ling-Jie; De Jonghe, Steven; Daelemans, Dirk; Herdewijn, Piet

2016-05-01

A series of novel aryloxyphosphoramidate nucleoside prodrugs based on l-aspartic acid and l-glutamic acid as amino acid motif has been synthesized and evaluated for antitumoral activity. Depending on the cancer cell line studied and on the nature of the parent nucleoside compound (gemcitabine, 5-iodo-2'-deoxy-uridine, floxuridine or brivudin), the corresponding ProTides are endowed with an improved or decreased cytotoxic activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Glutamate signalling and secretory phospholipase A2 modulate the release of arachidonic acid from neuronal membranes

DEFF Research Database (Denmark)

Rodriguez De Turco, Elena B; Jackson, Fannie R; DeCoster, Mark A

2002-01-01

The lipid mediators generated by phospholipases A(2) (PLA(2)), free arachidonic acid (AA), eicosanoids, and platelet-activating factor, modulate neuronal activity; when overproduced, some of them become potent neurotoxins. We have shown, using primary cortical neuron cultures, that glutamate...... and secretory PLA(2) (sPLA(2)) from bee venom (bv sPLA(2)) and Taipan snake venom (OS2) elicit synergy in inducing neuronal cell death. Low concentrations of sPLA(2) are selective ligands of cell-surface sPLA(2) receptors. We investigated which neuronal arachidonoyl phospholipids are targeted by glutamate......) and in minor changes in other phospholipids. A similar profile, although of greater magnitude, was observed 20 hr posttreatment. Glutamate (80 microM) induced much less mobilization of (3)H-AA than did sPLA(2) and resulted in a threefold greater degradation of (3)H-AA PE than of (3)H-AA PC by 20 hr...

Introduction to the Glutamate-Glutamine Cycle

DEFF Research Database (Denmark)

Sonnewald, Ursula; Schousboe, Arne

2016-01-01

. This is metabolically impossible unless it is assumed that at least two distinct pools of these amino acids exist. This combined with the finding that the enzyme synthesizing glutamine from glutamate was expressed in astrocytes but not in neurons formed the basis of the notion that a cycle must exist in which glutamate......The term 'glutamate-glutamine cycle' was coined several decades ago based on the observation that using certain (14)C-labeled precursors for studies of brain metabolism the specific radioactivity of glutamine generated from glutamate was higher than that of glutamate, its immediate precursor...... released from neurons is transported into astrocytes, converted to glutamine which is subsequently returned to neurons and converted to glutamate by an enzyme the activity of which is much higher in neurons than in astrocytes. Originally this cycle was supposed to function in a stoichiometric fashion...

Introduction to the Glutamate-Glutamine Cycle

DEFF Research Database (Denmark)

Sonnewald, Ursula; Schousboe, Arne

2016-01-01

released from neurons is transported into astrocytes, converted to glutamine which is subsequently returned to neurons and converted to glutamate by an enzyme the activity of which is much higher in neurons than in astrocytes. Originally this cycle was supposed to function in a stoichiometric fashion......The term 'glutamate-glutamine cycle' was coined several decades ago based on the observation that using certain (14)C-labeled precursors for studies of brain metabolism the specific radioactivity of glutamine generated from glutamate was higher than that of glutamate, its immediate precursor....... This is metabolically impossible unless it is assumed that at least two distinct pools of these amino acids exist. This combined with the finding that the enzyme synthesizing glutamine from glutamate was expressed in astrocytes but not in neurons formed the basis of the notion that a cycle must exist in which glutamate...

Effects of Memantine, an NMDA Antagonist, on Metabolic Syndromes in Female NMRI Mice

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Naser Osanloo

2015-10-01

Results: The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight and eating latency, but had no effect on food intake or weight. The dose and site-dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels and water and food intake, or else had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal’s weight and inhibited the effects of stress on fecal weight and eating latency. Discussion: The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, with gender playing a significant role in producing this effect.

pH-jump induced α-helix folding of poly-L-glutamic acid

International Nuclear Information System (INIS)

Donten, Mateusz L.; Hamm, Peter

2013-01-01

Highlights: ► pH-jump as truly biomimetic tool to initiate non-equilibrium dynamics of biomolecules. ► Design criteria to widen the applicability of pH-jumps are developed. ► Folding of poly-L-Glu in dependence of starting pH, pH jump size and helix length. ► Length dependence provides strong evidence for a nucleation–propagation scenario. - Abstract: pH jumps are a truly biomimetic technique to initiate non-equilibrium dynamics of biomolecules. In this work, the pH jump induced α-helix folding of poly-L-glutamic acid is investigated upon proton release from o-nitrobenzaldehyde. The aim of this work is twofold: On the one hand, design criteria of pH jump experiments are discussed, on the other hand, the folding mechanism of poly-L-glutamic acid is clarified by probing the IR response of the amide I band. Its folding kinetics is studied in dependence of the starting pD, the size of the pD jump and the length of the helix. While no dependence on the first two parameters could be detected, the folding time varies from 0.6 μs to 1.8 μs for helix lengths of 20 residue to 440 residue, respectively. It converges to a long-length limit at about 50 residue, a result which is attributed to a nucleation–propagation mechanism

Effect of supersaturation on L-glutamic acid polymorphs under droplet-based microchannels

Science.gov (United States)

Jiang, Nan; Wang, Zhanzhong; Dang, Leping; Wei, Hongyuan

2016-07-01

Supersaturation is an important controlling factor for crystallization process and polymorphism. Droplet-based microchannels and conventional crystallization were used to investigate polymorphs of L-gluatamic acid in this work. The results illustrate that it is easy to realize the accurate and rapid control of the crystallization temperature in the droplets, which is especially beneficial to heat and mass transfer during crystallization. It is also noted that higher degree of supersaturation favors the nucleation of α crystal form, while lower degree of supersaturation favors the nucleation of β crystal form under droplet-based microchannels for L-gluatamic acid. In addition, there is a different nucleation behavior to be found under droplet-based microchannels both for the β form and α form of L-glutamic acid. This new finding can provide important insight into the development and design of investigation meanings for drug polymorph.

Poly(γ-glutamic acid) and poly(γ-glutamic acid)-based nanocomplexes enhance type II collagen production in intervertebral disc.

Science.gov (United States)

Antunes, Joana C; Pereira, Catarina Leite; Teixeira, Graciosa Q; Silva, Ricardo V; Caldeira, Joana; Grad, Sibylle; Gonçalves, Raquel M; Barbosa, Mário A

2017-01-01

Intervertebral disc (IVD) degeneration often leads to low back pain, which is one of the major causes of disability worldwide, affecting more than 80% of the population. Although available treatments for degenerated IVD decrease symptoms' progression, they fail to address the underlying causes and to restore native IVD properties. Poly(γ-glutamic acid) (γ-PGA) has recently been shown to support the production of chondrogenic matrix by mesenchymal stem/stromal cells. γ-PGA/chitosan (Ch) nanocomplexes (NCs) have been proposed for several biomedical applications, showing advantages compared with either polymer alone. Hence, this study explores the potential of γ-PGA and γ-PGA/Ch NCs for IVD regeneration. Nucleotomised bovine IVDs were cultured ex vivo upon injection of γ-PGA (pH 7.4) and γ-PGA/Ch NCs (pH 5.0 and pH 7.4). Tissue metabolic activity and nucleus pulposus DNA content were significantly reduced when NCs were injected in acidic-buffered solution (pH 5.0). However, at pH 7.4, both γ-PGA and NCs promoted sulphated glycosaminoglycan production and significant type II collagen synthesis, as determined at the protein level. This study is a first proof of concept that γ-PGA and γ-PGA/Ch NCs promote recovery of IVD native matrix, opening new perspectives on the development of alternative therapeutic approaches for IVD degeneration.

Danish children born with glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies at birth had an increased risk to develop type 1 diabetes

DEFF Research Database (Denmark)

Eising, Stefanie; Nilsson, Anita; Carstensen, Bendix

2011-01-01

A large, population-based case-control cohort was used to test the hypothesis that glutamic acid decarboxylase-65 (GAD65) and islet antigen-2 autoantibodies (IA-2A) at birth predict type 1 diabetes.......A large, population-based case-control cohort was used to test the hypothesis that glutamic acid decarboxylase-65 (GAD65) and islet antigen-2 autoantibodies (IA-2A) at birth predict type 1 diabetes....

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes

DEFF Research Database (Denmark)

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies...

An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

Directory of Open Access Journals (Sweden)

Xinglong Gu

2016-01-01

Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

Limbic encephalitis with antibodies to glutamic acid decarboxylase presenting with brainstem symptoms

Directory of Open Access Journals (Sweden)

Faruk Incecik

2015-01-01

Full Text Available Limbic encephalitis (LE is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. LE associated with glutamic acid decarboxylase antibodies (anti-GAD is rare in children. Here, we characterized the clinical and laboratory features of a patient presenting with brainstem involvement with non-paraneoplastic LE associated with anti-GAD antibodies. In our patient, after plasma exchange, we determined a dramatic improvement of the neurological deficits.

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

Science.gov (United States)

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

NMDA or 5-HT receptor antagonists impair memory reconsolidation and induce various types of amnesia.

Science.gov (United States)

Nikitin, V P; Solntseva, S V; Kozyrev, S A; Nikitin, P V; Shevelkin, A V

2018-06-01

Elucidation of amnesia mechanisms is one of the central problems in neuroscience with immense practical application. Previously, we found that conditioned food presentation combined with injection of a neurotransmitter receptor antagonist or protein synthesis inhibitor led to amnesia induction. In the present study, we investigated the time course and features of two amnesias: induced by impairment of memory reconsolidation using an NMDA glutamate receptor antagonist (MK-801) and a serotonin receptor antagonist (methiothepin, MET) on snails trained with food aversion conditioning. During the early period of amnesia (types of amnesia. Retraining an on 1st or 3rd day of amnesia induction facilitated memory formation, i.e. the number of CS + US pairings was lower than at initial training. On the 10th or 30th day after the MET/reminder, the number of CS + US pairings did not change between initial training and retraining. Retraining on the 10th or 30th day following the MK-801/reminder in the same or a new context of learning resulted in short, but not long-term, memory, and the number of CS + US pairings was higher than at the initial training. This type of amnesia was specific to the CS we used at initial training, since long-term memory for another kind of CS could be formed in the same snails. The attained results suggest that disruption of memory reconsolidation using antagonists of serotonin or NMDA glutamate receptors induced amnesias with different abilities to form long-term memory during the late period of development. Copyright © 2018 Elsevier B.V. All rights reserved.