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PubMed2005

Protection of cortical cells by equine estrogens against glutamate-induced excitotoxicity is mediated through a calcium independent mechanism.

BACKGROUND: High concentrations of glutamate can accumulate in the brain and may be involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. This form of neurotoxicity involves changes in the regulation of cellular calcium (Ca2+) and generation of free radicals such as peroxynitrite (ONOO-). Estrogen may protect against glutamate-induced cell death by reducing the excitotoxic Ca2+ influx associated with glutamate excitotoxicity. In this study, the inhibition of N-methyl-D-aspartate (NMDA) receptor and nitric oxide synthase (NOS) along with the effect of 17beta-estradiol (17beta-E2) and a more potent antioxidant Delta8, 17beta-estradiol (Delta8, 17beta-E2) on cell viability and intracellular Ca2+ ([Ca2+]i), following treatment of rat cortical cells with glutamate, was investigated. RESULTS: Primary rat cortical cells were cultured for 7-12 days in Neurobasal medium containing B27 supplements. Addition of glutamate (200 microM) decreased cell viability to 51.3 +/- 0.7% compared to control. Treatment with the noncompetitive NMDAR antagonist, MK-801, and the NOS inhibitor, L-NAME, completely prevented cell death. Pretreatment (24 hrs) with 17beta-E2 and Delta8, 17beta-E2 (0.01 to 10 microM) significantly reduced cell death. 17beta-E2 was more potent than Delta8, 17beta-E2. Glutamate caused a rapid 2.5 fold increase in [Ca2+]i. Treatment with 0.001 to 10 microM MK-801 reduced the initial Ca2+ influx by 14-41% and increased cell viability significantly. Pretreatment with 17beta-E2 and Delta8, 17beta-E2 had no effect on Ca2+ influx but protected the cortical cells against glutamate-induced cell death. CONCLUSION: Glutamate-induced cell death in cortical cultures can occur through NMDAR and NOS-linked mechanisms by increasing nitric oxide and ONOO-. Equine estrogens: 17beta-E2 and Delta8, 17beta-E2, significantly protected cortical cells against glutamate-induced excitotoxicity by a mechanism that appears to be independent of Ca2+ influx. To our knowledge, this is a first such observation. Whether the decrease in NOS related products such as ONOO-, is a mechanism by which estrogens protect against glutamate toxicity, remains to be investigated. Estrogen replacement therapy in healthy and young postmenopausal women may protect against neurodegenerative diseases by these mechanisms.

Animals↗
PubMed2000

Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: II. Glutamate (Ant)agonists.

OBJECTIVE: To summarize the published preclinical and clinical data that suggest the possible use of glutamate receptor agonists or antagonists as novel antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included. DATA SYNTHESIS: The standard antipsychotic drugs, whose clinical activity correlates with affinity for dopamine D2 receptors, alleviate some of the positive symptoms of schizophrenia, but have limited impact on negative symptoms. Several lines of evidence implicate glutamate-receptor system dysfunction(s) in schizophrenia, either as causative or contributory factors. In addition, several standard antipsychotic drugs modulate glutamate or glutamate receptor activity, suggesting an alternative view of their mechanism of antipsychotic action. Preliminary studies have shown that drugs which modulate glutamate brain concentrations have positive effects in animal models of schizophrenia. CONCLUSIONS: A role for glutamate in the pathogenesis or pharmacotherapy of schizophrenia is suggested from anatomic (interactions between glutamatergic and dopaminergic systems in relevant brain regions), physiologic (implication of glutamate-receptor dysfunction), and pharmacologic (modulation of glutamate or glutamate receptors) evidence. Therefore, compounds that function at glutamate receptors might represent a novel approach to the treatment of the disease or to the amelioration of symptoms, either as monotherapy or as an adjunct to dopamine D2 receptor antagonists.

Animals↗
PubMed2005

In vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells is inhibited by the ethylmercury-containing preservative thimerosal.

Thimerosal, also known as thimersal, Merthrolate, or sodiumethyl-mercurithiosalicylate, is an organic mercurial compound that is used in a variety of commercial as well as biomedical applications. As a preservative, it is used in a number of vaccines and pharmaceutical products. Its active ingredient is ethylmercury. Both inorganic and organic mercurials are known to interfere with glutamate homeostasis. Brain glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/ aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The effects of thimerosal on glutamate homeostasis have yet to be determined. As a first step in this process, we examined the effects of thimerosal on the transport of [3H]-d-aspartate, a nonmetabolizable glutamate analog, in Chinese hamster ovary (CHO) cells transfected with two glutamate transporter subtypes, GLAST (EAAT1) and GLT-1 (EAAT2). Additionally, studies were undertaken to determine the effects of thimerosal on mRNA and protein levels of these transporters. The results indicate that thimerosal treatment caused significant but selective changes in both glutamate transporter mRNA and protein expression in CHO cells. Thimerosal-mediated inhibition of glutamate transport in the CHO-K1 cell line DdB7 was more pronounced in the GLT-1-transfected cells compared with the GLAST- transfected cells. These studies suggest that thimerosal accumulation in the central nervous system might contribute to dysregulation of glutamate homeostasis.

Amino Acid Transport System X-AG↗
PubMed2006

Intersubunit interactions in EAAT4 glutamate transporters.

Excitatory amino acid transporters (EAATs) play a central role in the termination of synaptic transmission and in extracellular glutamate homeostasis in the mammalian CNS. A functional transporter is assembled as oligomer consisting of three subunits, each of which appears to transport glutamate independently from the neighboring subunits. EAATs do not only sustain a secondary-active glutamate transport but also function as anion channel. We here address the question whether intersubunit interactions play a role in pore-mediated anion conduction. We expressed a neuronal isoform, EAAT4, heterologously in Xenopus oocytes and mammalian cells and measured glutamate flux and anion currents under various concentrations of Na+ and glutamate. EAAT4 anion channels are active in the absence of both substrates, and increasing concentrations activate EAAT4 anion currents with a sigmoidal concentration dependence. Because only one glutamate molecule is cotransported per uptake cycle, the cooperativity between glutamate binding sites most likely arises from an interaction between different carrier domains. This interaction is modified by two point mutations close to the putative glutamate binding site, G464S and Q467S. Both mutations alter the dissociation constants and Hill coefficient of the substrate dependence of anion currents, leaving the concentration dependence of glutamate uptake unaffected. Our results demonstrate that glutamate carriers cooperatively interact during anion channel activation.

Animals↗
PubMed1997

Control of the phosphorylation of the astrocyte marker glial fibrillary acidic protein (GFAP) in the immature rat hippocampus by glutamate and calcium ions: possible key factor in astrocytic plasticity.

The present review describes recent research on the regulation by glutamate and Ca2+ of the phosphorylation state of the intermediate filament protein of the astrocytic cytoskeleton, glial fibrillary acidic protein (GFAP), in immature hippocampal slices. The results of this research are discussed against a background of modern knowledge of the functional importance of astrocytes in the brain and of the structure and dynamic properties of intermediate filament proteins. Astrocytes are now recognized as partners with neurons in many aspects of brain function with important roles in neural plasticity. Site-specific phosphorylation of intermediate filament proteins, including GFAP, has been shown to regulate the dynamic equilibrium between the polymerized and depolymerized state of the filaments and to play a fundamental role in mitosis. Glutamate was found to increase the phosphorylation state of GFAP in hippocampal slices from rats in the post-natal age range of 12-16 days in a reaction that was dependent on external Ca2+. The lack of external Ca2+ in the absence of glutamate also increased GFAP phosphorylation to the same extent. These effects of glutamate and Ca2+ were absent in adult hippocampal slices, where the phosphorylation of GFAP was completely Ca(2+)-dependent. Studies using specific agonists of glutamate receptors showed that the glutamate response was mediated by a G protein-linked group II metabotropic glutamate receptor (mGluR). Since group II mGluRs do not act by liberating Ca2+ from internal stores, it is proposed that activation of the receptor by glutamate inhibits Ca2+ entry into the astrocytes and consequently down-regulates a Ca(2+)-dependent dephosphorylation cascade regulating the phosphorylation state of GFAP. The functional significance of these results may be related to the narrow developmental window when the glutamate response is present. In the rat brain this window corresponds to the period of massive synaptogenesis during which astrocytes are known to proliferate. Possibly, glutamate liberated from developing synapses during this period may signal an increase in the phosphorylation state of GFAP and a consequent increase in the number of mitotic astrocytes.

Animals↗
PubMed2005

Modulation of Na(+)-dependent glutamate transporter of murine astrocytes by inflammatory mediators.

Sodium-dependent glutamate transporters of astrocytes have been reported to maintain extracellular concentration of glutamate below toxic level in the central nervous system and to be concerned with neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In this study, the effects of inflammatory mediators including prostaglandin (PG) E2, interleukin (IL)-1beta and IL-6 on Na(+)-dependent L-glutamate transport of astrocytes were analyzed using primary murine astrocytes. The exposure of astrocytes to PGE2 for 24 h elicited a dose-dependent increase of L-glutamate uptake. Neither IL-beta nor IL-6 alone had any effect on L-glutamate uptake. However, IL-1beta enhanced the PGE2-induced increase of L-glutamate uptake. IL-6 suppressed the increase of L-glutamate uptake induced by PGE2. Kinetic analysis of L-glutamate uptake showed that PGE2 and PGE2 with IL-1beta increased V(max) value with no significant effect on Km value for Na(+)-dependent L-glutamate uptake. IL-6 suppressed the PGE2-induced V(max) value. These results suggest that IL-1beta, IL-6 and PGE2 modulate glutamate transport of astrocytes and play a role in the pathogenesis of neurodegenerative disorders such as ALS and AD.

Amino Acid Transport System X-AG↗
PubMed1999

Astrocytes: glutamate producers for neurons.

In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.

Animals↗
PubMed2000

Metabolic fate of glutamate and evaluation of flux through the 4-aminobutyrate (GABA) shunt in Aspergillus niger.

Accumulation of GABA and a concurrent block in the Krebs cycle suggest a functional GABA bypass in the acidogenic Aspergillus niger. Apart from the demonstration of enzyme machinery required, a direct measurement of flux through this glutamate decarboxylation loop was attempted. The distribution of carbon from glucose and glutamate was studied using A. niger mycelia grown on different media. The uptake and incorporation of (14)C label into organic acids and amino acids was followed by paper chromatography. Flow of label from glucose into citrate, glutamate and GABA increased in cells harvested at later stages of acidogenic growth. Very little citrate was derived from glutamate while ten times more label reached GABA from labeled glutamate. Radioactivity from L-[U-(14)C]glutamate and not from L-[1-(14)C]glutamate was recovered in GABA. This demonstrated that alpha-decarboxylation of L-glutamate was the source of GABA. Unless grown on GABA, A. niger mycelia did not take up externally supplied GABA. A direct measure of GABA shunt flux was thus not feasible. Therefore a combination of metabolite balance technique and the kinetic approach was applied to evaluate flux from glutamate to succinate in normal and acidogenic A. niger. The flux relative to TCA cycle was estimated by using uptake rate for radiolabeled glutamate, rate of accumulation of certain metabolites and the reactions of GABA metabolism. The analysis indicated that GABA shunt is operative in A. niger and its operation is enhanced during acidogenic growth of the fungus. This is the first report of an estimation of the flux through GABA shunt in a fungus.

Aspergillus niger↗
PubMed2000

Protective effect of bradykinin against glutamate neurotoxicity in cultured rat retinal neurons.

PURPOSE: To identify the localization and expression of bradykinin (BK)-B2 receptors in rat retina and examine the effects of BK on glutamate-induced neurotoxicity using cultured rat retinal neurons. METHODS: An immunohistochemical study using a specific antibody against BK-B2 receptor was performed with rat retina. Primary cultures were obtained from the retina of fetal rats (gestation day 17-19). Expression of BK-B2 receptor mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA obtained from cultured retinal neurons. Cultured cells were exposed to glutamate (1 mM) for 10 minutes and followed by incubation in glutamate-free medium for 1 hour. The effects of BK were assessed by simultaneous application of BK with glutamate. The neurotoxic effects on retinal cultures were quantitatively assessed by the trypan blue exclusion method. RESULTS: Immunohistochemical study demonstrated that BK-B2 receptors were expressed in the ganglion cell, inner nuclear layers, and outer nuclear layers. Furthermore, BK-B2 receptor mRNA expression was observed in cultured retinal neurons. Cell viability was markedly reduced by 10-minute exposure to 1 mM glutamate followed by a 1-hour incubation in glutamate-free medium. Simultaneous application of BK at concentrations of 0.001 to 1 microM with glutamate demonstrated dose-dependent protection against glutamate neurotoxicity. The protective action of BK (1 microM) was inhibited by simultaneous application of BK-B2 receptor antagonist, Hoe140 (1 microM). Furthermore, 1 microM BK had protective effects on neurotoxicity induced by 1 microM ionomycin, a calcium ionophore, and sodium nitroprusside (SNP, 500 microM), a nitric oxide (NO)-generating agent. However, BK did not inhibit neurotoxicity induced by 3-morpholinosydnonimine (SIN-1, 10 microM), an NO and oxygen radical donor. CONCLUSIONS: These results suggest that BK-B2 receptors were distributed in rat retinas and cultured retinal neurons and that BK had a protective action against glutamate neurotoxicity through BK-B2 receptors in cultured retinal neurons. It is suggested that BK-induced protection against glutamate neurotoxicity took place downstream to NO generation and upstream to oxygen radical generation.

Adrenergic beta-Antagonists↗
PubMed2000

The role of glutamate and nitric oxide in the reproductive neuroendocrine system.

The preovulatory surge of gonadotropin releasing hormone (GnRH) is essential for mammalian reproduction. Recent work has implicated the neurotransmitters glutamate and nitric oxide as having a key role in this process. Large concentrations of glutamate are found in several hypothalamic nuclei known to be important for GnRH release and glutamate receptors are also located in these key hypothalamic nuclei. Administration of glutamate agonists stimulate GnRH and LH release, while glutamate receptor antagonists attenuate the steroid-induced and preovulatory LH surge. Glutamate has also been implicated in the critical processes of puberty, hormone pulsatility, and sexual behavior. Glutamate is believed to elicit many of these effects by activating the release of the gaseous neurotransmitter, nitric oxide (NO). NO potently stimulates GnRH by activating a heme containing enzyme, guanylate cyclase, which in turn leads to increased production of cGMP and GnRH release. Recent work has focused on identifying anchoring and (or) clustering proteins that target glutamate receptors to the synapse and couple the glutamate-NO neurotransmission system. The present review will discuss these new findings, as well as the role of glutamate and nitric oxide in important mammalian reproductive events, with a focus on the hypothalamic control of preovulatory GnRH release.

Animals↗
PubMed2002

High affinity glutamate uptake in rat brain slices at experimental crush syndrome.

BACKGROUND: The pathogenesis of crush syndrome is severe traumatic damage to the organism accompanied by shock and stress, acute toxemia, etc. Glutamate has been shown to be implicated in excitotoxic neural death in various clinical settings. The high affinity glutamate uptake process plays a key role in normal synaptic transmission. The goal of our research was to determine the level of glutamate uptake in brain tissue slices after incorporation of [(14)C-U]glutamate. MATERIAL/METHODS: An experimental model of crush syndrome in Wistar male rats was caused by 2 hours of compression of femoral soft tissues using a special press with a force of 100 kg/1 kg of animal weight. Slices were prepared and glutamate uptake was assayed immediately after compression, and again at 2, 24, and 48 hours of decompression. RESULTS: The level of glutamate uptake in cerebral cortex and hypothalamus slices immediately after compression was reduced by 24% (p<0.05) and 31% (p<0.005) respectively. Glutamate uptake in cerebral cortex and hypothalamus was nearly at the same level as the intact group of animals (without compression). In cerebellum slices, glutamate uptake also increased, and in fact exceeded the level in the intact group by 17% (p<0.025). The level of glutamate uptake decreased in cerebral cortex, hypothalamus, and cerebellum slices by 45% (p<0.001), 28% (p<0.001,) and 25% (p<0.001) respectively, compared to the intact group of animals. CONCLUSIONS: Experimental crush syndrome promotes the reduction of the glutamate uptake level in brain tissue slices, such that cerebral cortex > hypothalamus > cerebellum.

Animals↗
PubMed2002

A high dietary intake of sodium glutamate as flavoring (ajinomoto) causes gross changes in retinal morphology and function.

The purpose of this study was to investigate the effects of glutamate accumulation in vitreous on retinal structure and function, due to a diet high in sodium glutamate. Three different diet groups were created, consisting of rats fed on a regular diet (diet A), a moderate excess of sodium glutamate diet (diet B) and a large excess of sodium glutamate diet (diet C). After 1, 3 and 6 months of the administration of these diets, amino acids concentrations in vitreous were analyzed. In addition, retinal morphology and function by electroretinogram (ERG) of three different diet groups were studied. Significant accumulation of glutamate in vitreous was observed in rats following addition of sodium glutamate to the diet as compared to levels with a regular diet. In the retinal morphology, thickness of retinal neuronal layers was remarkably thinner in rats fed on sodium glutamate diets than in those on a regular diet. TdT-dUTP terminal nick-end labelling (TUNEL) staining revealed significant accumulation of the positive staining cells within the retinal ganglion cell layers in retinas from diets B and C as compared with that from diet A. Similar to this, immunohistochemistry demonstrated increased expression of glial fibrillary acidic protein (GFAP) within the retinal inner layers from diets B and C as compared with diet A. Functionally, ERG responses were reduced in rats fed on a sodium glutamate diets as compared with those on a regular diet. The present study suggests that a diet with excess sodium glutamate over a period of several years may increase glutamate concentrations in vitreous and may cause retinal cell destruction.

Amino Acids↗
PubMed2003

Functional hemichannels in astrocytes: a novel mechanism of glutamate release.

Little is known about the expression and possible functions of unopposed gap junction hemichannels in the brain. Emerging evidence suggests that gap junction hemichannels can act as stand-alone functional channels in astrocytes. With immunocytochemistry, dye uptake, and HPLC measurements, we show that astrocytes in vitro express functional hemichannels that can mediate robust efflux of glutamate and aspartate. Functional hemichannels were confirmed by passage of extracellular lucifer yellow (LY) into astrocytes in nominal divalent cation-free solution (DCFS) and the ability to block this passage with gap junction blocking agents. Glutamate/aspartate release (or LY loading) in DCFS was blocked by multivalent cations (Ca2+, Ba2+, Sr2+, Mg2+, and La3+) and by gap junction blocking agents (carbenoxolone, octanol, heptanol, flufenamic acid, and 18alpha-glycyrrhetinic acid) with affinities close to those reported for blockade of gap junction intercellular communication. Glutamate efflux via hemichannels was also accompanied by greatly reduced glutamate uptake. Glutamate release in DCFS, however, was not significantly mediated by reversal of the glutamate transporter: release did not saturate and was not blocked by glutamate transporter blockers. Control experiments in DCFS precluded glutamate release by volume-sensitive anion channels, P2X7 purinergic receptor pores, or general purinergic receptor activation. Blocking intracellular Ca2+ mobilization by BAPTA-AM or thapsigargin did not inhibit glutamate release in DCFS. Divalent cation removal also induced glutamate release from intact CNS white matter (acutely isolated optic nerve) that was blocked by carbenoxolone, suggesting the existence of functional hemichannels in situ. Our results indicated that astrocyte hemichannels could influence CNS levels of extracellular glutamate with implications for normal and pathological brain function.

Adenosine Triphosphate↗
PubMed2003

Effects of L-glutamate supplementation mimic effects of fasting in the ischemic heart.

Endogenous glycogen stores are essential to maintain cell functions during myocardial ischemia.. Fasting and L-glutamate improve left ventricular function after an ischemic episode. We studied their effects on myocardial glycogen depletion during ischemia and on left ventricular function and glycogen resynthesis during reperfusion. We allocated 185 Wistar rats to 4 groups: 1) Control, 2) Fasting, 16-20 hours (Fast) 3) L-glutamate supplementation [100 mM] (Glt) or 4) Fasting + L-glutamate supplementation [100 mM]. n = 8-10 in each group. Hearts were mounted in an isolated perfused rat hearts model for 20 min stabilisation, 10/20/30 min ischemia and 60 min reperfusion. At each time point hearts were frozen in liquid nitrogen (-196 degrees C) within 2 seconds and myocardial contents of glycogen, lactate, alanine and glutamate were determined. Left ventricular pressure was measured continuously. Fasting and L-glutamate supplementation improved LV function after ischemia (Fast: p < 0.05, Glt: p < 0.01) and delayed myocardial glycogen depletion (Fast: p < 0.05, Glt: p < 0.01) compared to control. Decreased lactate accumulation and increased alanine content during ischemia were found in fasted (lactate: p < 0.05, alanine: p < 0.05) and L-glutamate supplemented (lactate: p < 0.01, alanine: p < 0.01) hearts compared to control. We did not find any additive effects of fasting and L-glutamate supplementation. In conclusion fasting and L-glutamate supplementation improve left ventricular function during reperfusion and delay myocardial glycogen depletion during ischemia. There were no additive effects of Fasting and L-glutamate supplementation. These finding suggest common metabolic pathways underlying the effects of L-glutamate supplementation and fasting.

Animals↗
PubMed2003

Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1.

Glutamate transporters remove glutamate from the extracellular space and maintain it below neurotoxic levels under normal conditions. However, the dynamics under ischemic conditions remain to be determined. In the present study, we evaluated the function of the glial glutamate transporter (GLT-1) during brain ischemia by using an in vivo brain microdialysis technique in GLT-1 mutant mice. A microdialysis probe was placed in the hippocampal CA1 of GLT-1 mutant and wild-type mice, and glutamate levels were measured during 5 and 20 min ischemia. The glutamate levels in mice lacking GLT-1 were significantly higher than the corresponding glutamate levels in wild-type mice during 5 min ischemia. Delayed neuronal death was induced in the CA1 of the mice lacking GLT-1 but not in the CA1 of the wild-type mice. When ischemia was elongated to the duration of 20 min, the glutamate levels in wild-type mice were significantly higher than the corresponding glutamate levels in mice lacking GLT-1 during the last 12.5 min of 20 min ischemia. Acute neuronal death was also observed in the CA1 of wild-type mice. These results suggest that GLT-1 takes up extracellular glutamate to protect neurons in the early stage of ischemia and then releases glutamate, triggering acute neuronal death, when ischemic conditions are elongated. The function of GLT-1 may change from neuroprotective to neurodegenerative during ischemia.

Animals↗
PubMed1979

Glutamate potential : differences from the excitatory junctional potential revealed by diltiazem and concanavalin A in crayfish neuromuscular junction.

1. The effect of diltiazem and concanavalin A (Con A) on the crayfish neuromuscular junction was investigated in order to compare the action of L-glutamate with that of the excitatory transmitter. 2. When diltiazem (0.3 nM) was added to the perfusion fluid, the iontophoretic glutamate potential was reduced to about half, whereas the amplitude of excitatory junctional potentials (EJPs) increased by about two times. 3. Dose-response curves of L-glutamate suggested that diltiazem acted in a non-competitive manner. The decrease in amplitude of the glutamate potential caused by diltiazem was not due to the acceleration of desensitization of the glutamate receptor. 4. The increase in amplitude of EJPs caused by diltiazem was due to the increase in membrane resistance. The quantal content and size of extracellular EJPs were not affected by diltiazem. 5. In normal saline, bath application of glutamate decreased the amplitude of both glutamate potentials and EJPs because of desensitization of the glutamate receptor. The decrease in amplitude of the glutamate potential was completely prevented by previous application of Con A (10(-6) M). On the other hand, Con A had no influence on the decrease in amplitude of EJPs. 6. Some possible explanations of these pharmacological differences between glutamate potentials and EJPs revealed by diltiazem and Con A are considered.

Animals↗
PubMed1995

Synapses of optic axons with GABA- and glutamate-containing elements in the optic tectum of Bufo marinus.

The central termination and the transmitter content of the optic fibers and the neurochemical nature of their synaptic targets was investigated in the optic tectum of the toad Bufo marinus. Retinal ganglion cells were retrogradely filled from the tectum with the fluorescent dye DiI and the retinal wholemounts were immunostained for glutamate. Most of the dye-filled cells could be double labeled. In addition, double-labeling for gamma-aminobutyric acid an glutamate were also made, when colocalization of these markers was not observed in the neurons of the retinal ganglion cell layer. In order to identify retinal terminals in the optic tectum, optic axons were retrogradely filled with horseradish peroxidase. Postembedding immunocytochemistry showed that 88% of the optic axon terminals were glutamate-like immunoreactive, 6% gamma-aminobutyric acid-immunoreactive and 6% were negative for both GABA and glutamate. Optic fibre terminals synapsed on gamma-aminobutyric acid- or glutamate-containing postsynaptic profiles (58% and 7%, respectively), while the rest on immunonegative elements. Optic fibres containing glutamate rarely synapsed with glutamate-like immunoreactive postsynaptic elements. In contrast, 67% of the gamma-aminobutyric acid-immunoreactive optic terminals synapsed onto gamma-aminobutyric acid-positive dendrites. It has been observed after combination of anterograde tracer transport and double-label immunocytochemistry, that 57% of the optic terminals synapsed on gamma-aminobutyric acid-immunoreactive elements and 38% on dendrites containing neither gamma-aminobutyric acid- nor glutamate-immunoreactive materials. These results suggest that (1) a large number of ganglion cells use glutamate and some gamma-aminobutyric acid as a transmitter, (2) a substantial proportion of the optic axons terminate on gamma-aminobutyric acid-containing inhibitory interneurons in the tectum, (3) some intrinsic neurons in the tectum are glutamate-like immunoreactive. We also propose, that (4) gamma-aminobutyric acid-immunoreactive optic axons may form an effective disinhibitory circuit in the tectum by synapsing preferentially with local inhibitory interneurons.

Animals↗
PubMed1995

Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat.

Dysfunction of excitatory glutamatergic neurotransmission has been implicated in the cause of hepatic encephalopathy. Brain microdialysis studies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute liver failure, have established that an increase in extracellular glutamate occurs but the mechanisms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial content, respectively), calcium-dependent glutamate release, and high-affinity, sodium-dependent glutamate uptake by synaptosomes prepared from rats with thioacetamide-induced encephalopathy. (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There was no significant difference in synaptosomal oxygen consumption, citrate synthase activity, glutamate release, total synaptosomal glutamate content, or the Kd for glutamate uptake between the encephalopathy group and the controls. However, there was a marked decrease in the maximal velocity of transport (Vmax) for glutamate uptake in synaptosomes from encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P < .05). The results of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could account for the elevated extracellular glutamate seen in the condition.

Animals↗