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PubMed1995

In vitro and in vivo evaluation of progesterone implants based on new biodegradable poly(glutamic and glutamate esters) copolymers.

New biodegradable polypeptidic copolymers of glutamic acid and tert-butyloxycarbonylmethyl glutamate were evaluated as implantable drug delivery systems. Three copolymers varying in degrees of esterification, which is inversely proportional to the number of glutamic residues, were selected for their range of hydrophilicity and biodegradation rates. Progesterone-containing implants were then prepared by means of an extrusion process and both in vitro and in vivo evaluations were performed. The effects of drug loading, nature, and pH of release medium were investigated. In vitro/in vivo correlations were established for some types of implants. Finally, mathematical fitting of the data, using published models, helped to better understand the mechanisms governing release.

Animals↗
PubMed1980

Pteroylpoly(gamma-glutamate) synthesis by Corynebacterium species. Purification and properties of folypoly(gamma-glutamate) synthetase.

Folylpolyglutamate synthetase was purified 7000-fold from extracts of Corynebacterium sp. The final preparation, which was greater than 95% pure, had a monomer molecular weight of 53,000. The purified enzyme catalyzed a MgATP-dependent addition of glutamate to a variety of reduced pteroate and reduced pteroylmono-, di-, and triglutamate substrates with the concomitant production of ADP and Pi. Although the specificity for the folate substrate was wide, the pteroate and pteroylmonoglutamate substrates were utilized much more effectively than the polyglutamate derivatives. The most effective substrates were tetrahydropteroate, tetrahydrofolate, and 5,10-methylene-tretrahydrofolate. The most effective diglutamate substrate was 5,10-methylene-tetrahydropteroyldiglutamate. Addition of more than one glutamate moiety was only observed with tetrahydropteroate and 5,10-methylene-tetrahydropteroylmono- and diglutamates as substrates. The enzyme exhibited a preference for ATP as the nucleotide substrate. dATP was almost as effective while UTP and CTP were less effective substitutes. The specificity for L-glutamate appeared to be absolute. Enzyme activity was maximal at about pH 10 and exhibited an absolute requirement for a monovalent cation, of which K+ was the most effective. Preliminary studies suggest that the active form of the enzyme may be a dimer and that K+ may be required to effect dimerization.

Adenosine Triphosphate↗
PubMed2006

Trigeminovestibular and trigeminospinal pathways in rats: retrograde tracing compared with glutamic acid decarboxylase and glutamate immunohistochemistry.

This study identified neurons in the sensory trigeminal complex with connections to the medial (MVN), inferior (IVN), lateral (LVN), and superior (SVN) vestibular nuclei or the spinal cord. Trigeminovestibular and trigeminospinal neurons were localized by injection of retrograde tracers. Immunohistochemical processing revealed gamma-aminobutyric acid (GABA)- and glutamate-containing neurons in these two populations. Trigeminovestibular neurons projecting to the MVN and the IVN were in the caudal principal nucleus (5P), pars oralis (5o), interpolaris (5i), and caudalis (5c) and scattered throughout the rostral 5P. Projections were bilateral to the IVN, with an ipsilateral dominance to the MVN, except from the rostral 5P, which was contralateral. Neurons projecting to the LVN were numerous in the ventral caudal 5P and the 5o and less abundant in the rostral 5P, 5i, and 5c. Our results suggested that only 5P and 5o project to the dorsal LVN. Neurons projecting to the SVN were in the dorsal 5P, 5o, and 5i but not in 5c. Trigeminospinal neurons were mainly in the ventral 5o and 5i and in the lateral 5c, rarely or never in 5P. Among trigeminovestibular neurons, most of the somas were immunoreactive for glutamate, but some reacted for GABA. Among trigeminospinal neurons, the number of somas immunoreactive for each of the two amino acids was similar. Trigeminal terminals were observed in contact with vestibulospinal neurons in the IVN and LVN, giving evidence of a trigeminovestibulospinal pathway. Therefore, inhibitory and excitatory facial inputs may contribute through trigeminospinal or trigeminovestibulospinal pathways to the control of head/neck movements.

Animals↗
PubMed2001

Molecular dynamics simulations of the conformational changes of the glutamate receptor ligand-binding core in the presence of glutamate and kainate.

Excitatory synaptic transmission is mediated by ionotropic glutamate receptors (iGluRs) through the induced transient opening of transmembrane ion channels. The three-dimensional structure of the extracellular ligand-binding core of iGluRs shares the overall features of bacterial periplasmic binding proteins (PBPs). In both families of proteins, the ligand-binding site is arranged in two domains separated by a cleft and connected by two peptide stretches. PBPs undergo a typical hinge motion of the two domains associated with ligand binding that leads to a conformational change from an open to a closed form. The common architecture suggests a similar closing mechanism in the ligand-binding core of iGluRs induced by the binding of specific agonists. Starting from the experimentally determined kainate-bound closed form of the S1S2 GluR2 construct, we have studied by means of molecular dynamics simulations the opening motion of the ligand-binding core in the presence and in the absence of both glutamate and kainate. Our results suggest that the opening/closing interdomain hinge motions are coupled to conformational changes in the insertion region of the transmembrane segments. These changes are triggered by the interaction of the agonists with the essential Glu 209 residue. A plausible mechanism for the coupling of agonist binding to channel gating is discussed.

Computer Simulation↗
PubMed1993

Lactate dehydrogenase and glutamate dehydrogenase activities in the circumventricular organs of rat brain following neonatal monosodium glutamate.

Glutamate (glu) an excitatory neurotransmitter amino acid, is present in high concentrations in the mammalian central nervous system and is the most abundant amino acid in our daily diet. In the present study the activities of lactate dehydrogenase (LDH) and glutamate dehydrogenase (GDH) were evaluated in the circumventricular organs (CVO) of the brain in 25-day-old rats following MSG administration at a dose of 4 mg/g b.wt during the first ten days of life. The results show the LDH activity increased to 265% of that in the control (p < 0.001), whereas GDH activity was significantly decreased (p < 0.05). The great elevation in LDH, a cytoplasmic marker enzyme, is apparently due to cytoskeletal changes brought about as a consequence of glu toxicity, whereas lowered GDH activity indicates altered glu homostasis in the blood-brain-barrier deficient areas following neonatal exposure to glu.

Animals↗
PubMed1985

Effect of phosphonic analogues of glutamic acid on glutamate decarboxylase.

Among the phosphonic analogues of glutamic acid, only 4-amino-4-phosphono butyric acid, the compound which shows the highest affinity for pyridoxal phosphate, inhibits competitively both Escherichia coli and rat brain glutamate decarboxylases. Phosphinothricin, 2-amino-4-(methylphosphino)butyric acid, is a strong inhibitor of the mammalian enzyme.

Animals↗
PubMed2000

Motor stimulation following bilateral injection of the group-I metabotropic glutamate receptor agonist into the dorsal striatum of rats: evidence against dependence on ionotropic glutamate receptors.

RATIONALE: Group-I metabotropic glutamate receptors (mGluRs) are densely expressed in the medium-sized spiny projection neurons of the striatum. Activation of the group-I mGluRs in the rat striatum with a selective group-I agonist, 3,5-dihydroxyphenylglycine (DHPG), produced locomotion and stereotypical behavior. OBJECTIVES: This study was designed to evaluate dependence of DHPG-stimulated motor behaviors on the ionotropic glutamate receptors [N-methyl-D-aspartate (NMDA) and kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)]. METHODS: In chronically cannulated rats, effects on motor activity of DHPG injected into the dorsal striatum were examined in the presence or absence of the antagonists selective for NMDA or kainate/AMPA receptors. RESULTS: Bilateral injections of DHPG (80 nmol) into the dorsal striatum induced a delayed locomotion followed by a prolonged stereotypical behavior characterized by the repetitive twitching movement of the head and forepaws. Blockade of NMDA receptors with intrastriatal injection of the NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 2.5 nmol), did not attenuate the behavioral changes induced by DHPG administration. Conversely, CPP unmasked an early onset of locomotion in response to DHPG injection as opposed to the delayed locomotion induced by DHPG in the absence of CPP. Pretreatment of rats with the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxaline2,3-dione (DNQX, 10 nmol), had no effect on DHPG-stimulated behaviors. CPP administered alone sedated animals, whereas DNQX given alone did not alter spontaneous behavioral activity. CONCLUSIONS: Motor stimulation induced by activation of the DHPG-sensitive group-I mGluRs in the striatum is independent upon co-activation of NMDA or kainate/AMPA receptors, since the NMDA or the kainate/AMPA receptor antagonist had no effect on DHPG-stimulated motor activity.

Animals↗
PubMed2001

Evidence that glutamate acting on presynaptic type-II metabotropic glutamate receptors alone does not fully account for the phenomenon of depolarisation-induced suppression of inhibition in cerebellar Purkinje cells.

Depolarisation-induced suppression of inhibition (DSI) is a form of short-term synaptic plasticity at gamma-aminobutyric-acid-(GABA)ergic synapses between principal neurons and interneurons in both the cerebellum and the hippocampus. The induction of DSI involves an intracellular calcium-dependent release of a retrograde messenger from the postsynaptic principal neuron (Purkinje cell/pyramidal cell in cerebellum/hippocampus) onto presynaptic interneurons, where it is thought to bind to guanine nucleotide-binding protein (G protein)-coupled receptors and subsequently reducing GABA release from these interneurons onto the postsynaptic principal neuron. Pharmacological studies have indicated that glutamate might be a retrograde messenger in both cerebellum and hippocampus, where, in the former at least, it seems to activate type-II metabotropic glutamate receptors (mGluRs). Using LY-341495, a recently described, highly specific and potent antagonist of type-II mGluRs, to block these receptors reduced DSI slightly, but significantly, in spite of the fact that this antagonist completely suppressed the effects of stimulating type-II mGluRs with a specific agonist. Activation of type II mGluRs alone thus cannot account fully for DSI in cerebellum and hence other mechanisms are involved in its induction. Such mechanisms probably involve an additional retrograde signal.

Amino Acids↗
PubMed1987

Immunocytochemical localizations of cytosolic and mitochondrial glutamic oxaloacetic transaminase isozymes in rat primary sensory neurons as a marker for the glutamate neuronal system.

The localization of cytosolic (s-) and mitochondrial (m-) glutamic oxaloacetic transaminase (GOT) was examined in the rat trigeminal, jugular and dorsal root ganglia by means of an indirect immunofluorescence method using antibodies specific for s- and m-GOT. Staining of s-GOT-like immunoreactivity was seen in giant, large, medium and small cells in these ganglia. On the other hand, m-GOT-like immunoreactivity was not seen in them. The distribution of GOT suggests that glutamate may be a transmitter released from primary sensory neurons.

Animals↗
PubMed1994

Effects of systemic or oral ad libitum monosodium glutamate administration on striatal glutamate release, as measured using microdialysis in freely moving rats.

We examined effects of high doses of monosodium glutamate (MSG) on extracellular glutamate levels in rat striata, using in vivo microdialysis. Parenteral doses (0.5, 1.0 and 2.0, but not 0.25, g/kg, i.p.) caused dose- and time-dependent increases, peaking after 40 min (at 174 +/- 47%, 485 +/- 99% and 1021 +/- 301% of basal levels, respectively). In contrast, dietary MSG (1.49 +/- 0.10 g/kg/h) was ineffective.

Administration, Oral↗
PubMed1984

Glutamate-containing dipeptides enhance specific binding at glutamate receptors and inhibit specific binding at kainate receptors in rat brain.

The dipeptide, L-phenylalanyl-L-glutamate (PG), augments the specific binding of the excitatory amino acid receptor antagonist, [3H]2-amino-7-phosphonoheptanoic acid (APH), to rat forebrain membranes by 5-fold at 100 microM with an EC50 of 4.9 microM. The increase in the specific binding of [3H]AHP induced by PG results exclusively from an increase in Bmax. In contrast, PG inhibits the specific binding of [3H]kainic acid to forebrain membranes with a Ki of 6.8 microM. Of several related peptides examined, active ones affected the two receptor sites in a reciprocal fashion. The results suggest an allosteric interaction between [3H]APH and kainate receptors modulated by glutamate-containing peptides.

2-Amino-5-phosphonovalerate↗
PubMed1991

Biological actions of beta-hydroxy-l-glutamic acid, a synthesized structural analogue of glutamic acid.

1. Biological actions of beta-hydroxy-L-glutamic acid (BHGA), a synthesized analog of L-glutamic acid (Glu), were examined using voltage-clamp, electrophysiological and binding assay techniques. 2. Application of BHGA to the voltage-clamped snail neurons elicited an inward current which was blocked by Na(+)-free saline but not by Co(2+)-substituted Ca(2+)-free saline in the voltage-clamped snail neurons. 3. This response exhibited a potency about 10 times stronger than Glu, and was not completely blocked by DL-2-amino-5-phosphonovaleric acid or kynurenic acid. 4. Intraventricular injection of BHGA caused burst discharges in the electrocorticograph (ECoG) of rats whose pattern was similar to that elicited by Glu, but quite different from the ECoG charges induced by NMDA, quisqualic acid, or kainic acid. 5. Receptor binding assays using specific radioactive ligands showed that the binding affinity of BHGA to the Glu receptor was different from that of other agonists tested.

Animals↗
PubMed1982

Plasma and brain levels of glutamate and pyroglutamate after oral monosodium glutamate to rats.

Plasma and brain levels of pyroglutamate (Py), a compound connected with the pathway of glutamate (GA) metabolism, were measured in rats after oral administration of monosodium glutamate (MSG) or Py. Oral MSG (1 g/kg) was followed by only a small rise in plasma Py levels. No increase of Py or GA brain levels was observed in these experimental conditions. Oral administration of Py (0.05, 0.5 and 1 g/kg) resulted in a marked dose-dependent increase of plasma Py, but no increase of plasma or brain GA levels. However, Py accumulated in brain in a dose-related manner. After 0.05 mg/kg the basal brain levels remained unchanged at all the times considered. Rat brain Py levels significantly increased when the oral dose of Py was raised to 0.5 g/kg. Peak brain levels were reached at 240 min, and were about 3 and 4 times the basal levels after 0.5 and 1 g/kg, respectively.

Administration, Oral↗
PubMed2005

Among the twenty classical L-amino acids, only glutamate directly activates metabotropic glutamate receptors.

Under pathophysiological conditions, cellular amino acids can be profusely released from cells into the cerebral interstitial space. Because several class-C G protein coupled receptors (GPCRs) display a broad natural ligand spectrum, being sensitive to more than one endogenous ligand, we wondered whether the related metabotropic glutamate (mGlu) receptors could be modulated by various types of L-amino acids, allowing them to sense large increase in extracellular amino acid concentration. Here, the agonist, antagonist and allosteric effects of the twenty classical L-amino acids were evaluated on the eight mGlu receptor subtypes. We show that, in addition to glutamate (Glu), cysteine, aspartate and asparagine also lead to the activation of mGlu3, 4 and 5. Interestingly, our data demonstrate that the effect of these three amino acids did not result from a direct activation of the receptors, but from an indirect action involving Glu-transporters/exchangers. These data first demonstrate that mGlu receptors, unlike other class-C GPCRs, display an extremely high selectivity towards one ligand. Moreover, our results also show that Glu transport systems allow mGlu receptors to sense large increase in the extracellular concentration of some amino acids. Such a system will certainly lead to a large increase in some mGlu receptor activity under pathological conditions, such as seizure, ischemia or other brain injuries.

Amino Acid Transport System X-AG↗
PubMed2001

MK-801 is cytotoxic to microglia in vitro and its cytotoxicity is attenuated by glutamate, other excitotoxic agents and atropine. Possible presence of glutamate receptor and muscarinic receptor on microglia.

We examined the cytotoxicity of MK-801 on cultured microglia and demonstrated its cytotoxicity. Cytotoxicity of MK-801 was reduced by the addition of L-glutamate, kainate and NMDA. The action of MK-801 was due to the direct action of microglia. It suggested the existence of glutamate receptor in microglia. Cytotoxicity of MK-801 was reduced by the addition of atropine sulfate which suggested the presence of muscarinic receptor in microglia.

Animals↗
PubMed1997

Distribution and projection of the medullary cardiovascular control neurons containing glutamate, glutamic acid decarboxylase, tyrosine hydroxylase and phenylethanolamine N-methyltransferase in rats.

This study was aimed at showing the distribution and projection of the medullary cardiovascular control neurons that contain a standard neurotransmitter or a related enzyme in the rat. A small amount of HRP was injected into either the depressor area of the caudal ventrolateral medulla (D-CVLM) or the pressor area of the rostral ventrolateral medulla (P-RVLM). Using an immunohistochemical method, we identified HRP-labelled neurons which were stained with antiserum to glutamate (Glu), glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH) or phenylethanolamine N-methyltransferase (PNMT). Our findings are summarized as follows. (1) The Glu-containing neurons in the nucleus tractus solitararii (NTS) project to the D-CVLM (n = 279, 100% assumed as a standard value) and P-RVLM (n = 225, 81% against the standard), indicating divergent excitatory projection. (2) The GAD-containing neurons in the NTS (n = 74, 27% against the standard) project to the P-RVLM, indicating the convergent inhibitory projection. (3) The projections of the TH-containing neurons from the NTS (n = 19, 7% against the standard) and CVLM (n = 4, 1% against the standard) to the P-RVLM are weaker than those of the GAD-containing neurons, suggesting that the catecholaminergic neurons play a minor role in inhibition of the sympathetic activity of the P-RVLM neurons. These results suggest that the glutamatergic NTS neurons excite both the P-RVLM and D-CVLM neurons, and the gamma-aminobutyric acid (GABA)ergic NTS and CVLM neurons inhibit the sympathetic activity of the P-RVLM neurons.

Animals↗
PubMed2003

Neonatal monosodium glutamate treatment modifies glutamic acid decarboxylase activity during rat brain postnatal development.

Monosodium glutamate (MSG) produces neurodegeneration in several brain regions when it is administered to neonatal rats. From an early embryonic age to adulthood, GABA neurons appear to have functional glutamatergic receptors, which could convert them in an important target for excitotoxic neurodegeneration. Changes in the activity of the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), have been shown after different neuronal insults. Therefore, this work evaluates the effect of neonatal MSG treatment on GAD activity and kinetics in the cerebral cortex, striatum, hippocampus and cerebellum of the rat brain during postnatal development. Neonatal MSG treatment decreased GAD activity in the cerebral cortex at 21 and 60 postnatal days (PD), mainly due to a reduction in the enzyme affinity (K(m)). In striatum, the GAD activity and the enzyme maximum velocity (V(max)) were increased at PD 60 after neonatal MSG treatment. Finally, in the hippocampus and cerebellum, the GAD activity and V(max) were increased, but the K(m) was found to be lower in the experimental group. The results could be related to compensatory mechanisms from the surviving GABAergic neurons, and suggest a putative adjustment in the GAD isoform expression throughout the development of the postnatal brain, since this enzyme is regulated by the synaptic activity under physiological and/or pathophysiological conditions.

Animals↗