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At least 289 records · Page 16Linked to original sources
PubMed2000

Ionotropic glutamate receptors trigger microvesicle-mediated exocytosis of L-glutamate in rat pinealocytes.

Rat pinealocytes receive noradrenergic innervation that stimulates melatonin synthesis. Besides melatonin, we showed previously that pinealocytes accumulate L-glutamate in microvesicles and secrete it through an exocytic mechanism. The secreted glutamate binds to the class II metabotropic glutamate receptor and inhibits norepinephrine-stimulated melatonin synthesis in neighboring pinealocytes through an inhibitory cyclic AMP cascade. In this study, it was found that, in addition to metabotropic receptors, pinealocytes express functional ionotropic receptors. RT-PCR and northern analyses indicated the expression of mRNA for GluR1, KA2, and NR2C in pineal gland. The presence of GluR1 protein was confirmed by immunological techniques, but neither KA2 nor NR2C was detected. Consistent with this observation, the presence of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate, non-N-methyl-D-aspartate receptor agonists, transiently stimulated increased the intracellular Ca(2+) concentration of cultured pinealocytes, whereas N-methyl-D-aspartate did not. These responses were prevented by 6-cyano-7-nitroquinoxaline-2,3-dione, a selective antagonist for non-N-methyl-D-aspartate receptors, by L-type Ca(2+) channel blockers such as nifedipine, or by omitting Ca(2+) or Na(+) in the medium. In the presence of Ca(2+) and Na(+), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate evoked glutamate secretion from the cultured cells, which was prevented by 6-cyano-7-nitroquinoxaline-2,3-dione, L-type Ca(2+) channel blockers, type E or B botulinum neurotoxin, or incubation at <20 degrees C. These results strongly suggest that GluR1 is functionally expressed in pinealocytes and triggers microvesicle-mediated exocytosis of L-glutamate via activation of L-type Ca(2+) channels. It is possible that GluR1 participates in a signaling cascade that enhances and expands the L-glutamate signal throughout the pineal gland.

Animals↗
PubMed2000

Protein phosphatase 1 and 2A inhibitors prolong the switch in the control of glutamate release by group I metabotropic glutamate receptors: characterization of the inhibitory pathway.

We have addressed the role of protein phosphatases (PPs) in the modulation of the switch in glutamate release observed after repetitive stimulation of group I metabotropic glutamate receptors (mGluRs). In cerebrocortical nerve terminals the agonist (S:)-3, 5-dihydroxyphenylglycine facilitated evoked glutamate release. However, a second stimulation, 5 min later, reduced rather than facilitated this release. This switch in the control of glutamate release was reversed when a 30-min interval was left between stimulations. Inhibition of the endogenous PPs, PP1 and PP2A, with calyculin A and okadaic acid prevented the recovery of the facilitatory response and maintained the receptor permanently coupled to the inhibitory pathway. The inhibitors of PP2B, cyclosporin A and cypermethrine, had no effect. The inhibition of glutamate release was insensitive to pertussis toxin and was the result of the loss of the release component coupled to N-type Ca(2+) channels. This inhibitory action was suppressed by addition of the protein kinase C activator 4beta-phorbol 12,13-dibutyrate. We conclude that the balance between protein kinase and phosphatase activity at the nerve terminal plays a key role in accommodating the modulation of glutamate release by group I mGluRs.

4-Aminopyridine↗
PubMed2004

In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands.

The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo.

Amino Acids↗
PubMed1999

Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal.

Na(+)-dependent transporters for glutamate exist on astrocytes (EAAT1 and EAAT2) and neurons (EAAT3). These transporters presumably assist in keeping the glutamate concentration low in the extracellular fluid of brain. Recently, Na(+)-dependent glutamate transport was described on the abluminal membrane of the blood-brain barrier. To determine whether the above-mentioned transporters participate in glutamate transport of the blood-brain barrier, total RNA was extracted from bovine cerebral capillaries. cDNA for EAAT1, EAAT2, and EAAT3 was observed, indicating that mRNA was present. Western blot analysis demonstrated all three transporters were expressed on abluminal membranes, but none was detectable on luminal membranes of the blood-brain barrier. Measurement of transport kinetics demonstrated voltage dependence, K(+)-dependence, and an apparent K(m) of 14 microM (aggregate of the three transporters) at a transmembrane potential of -61 mV. Inhibition of glutamate transport was observed using inhibitors specific for EAAT2 (kainic acid and dihydrokainic acid) and EAAT3 (cysteine). The relative activity of the three transporters was found to be approximately 1:3:6 for EAAT1, EAAT2, and EAAT3, respectively. These transporters may assist in maintaining low glutamate concentrations in the extracellular fluid.

ATP-Binding Cassette Transporters↗
PubMed2004

Effects of glutamate transport substrates and glutamate receptor ligands on the activity of Na-/K(+)-ATPase in brain tissue in vitro.

1. It has been suggested that Na+/K(+)-ATPase and Na(+)-dependent glutamate transport (GluT) are tightly linked in brain tissue. In the present study, we have investigated Na+/K(+)-ATPase activity using Rb+ uptake by 'minislices' (prisms) of the cerebral cortex. This preparation preserves the morphology of neurons, synapses and astrocytes and is known to possess potent GluT that has been well characterized. Uptake of Rb+ was determined by estimating Rb+ in aqueous extracts of the minislices, using atomic absorption spectroscopy. 2. We determined the potencies of several known substrates/inhibitors of GluT, such as L-trans-pyrrolidine-2,4-dicarboxylate (LtPDC), DL-threo-3-benzyloxyaspartic acid, (2S,3S,4R)-2-(carboxycyclopropyl)-glycine (L-CCG III) and L-anti,endo-3,4-methanopyrrolidine dicarboxylic acid, as inhibitors of [3H]-L-glutamate uptake by cortical prisms. In addition, we established the susceptibility of GluT, measured as [3H]-L-glutamate uptake in brain cortical prisms, to the inhibition of Na+/K(+)-ATPase by ouabain. Then, we tested the hypothesis that the Na+/K(+)-ATPase (measured as Rb+ uptake) can respond to changes in the activity of GluT produced by using GluT substrates as GluT-specific pharmacological tools. 3. The Na+/K(+)-ATPase inhibitor ouabain completely blocked Rb+ uptake (IC50 = 17 micromol/L), but it also potently inhibited a fraction of GluT (approximately 50% of [3H]-L-glutamate uptake was eliminated; IC50 < 1 micromol/L). 4. None of the most commonly used GluT substrates and inhibitors, such as L-aspartate, D-aspartate, L-CCG III and LtPDC (all at 500 micromol/L), produced any significant changes in Rb+ uptake. 5. The N-methyl-D-aspartate (NMDA) receptor agonists (R,S)-(tetrazol-5-yl)-glycine and NMDA decreased Rb+ uptake in a manner compatible with their known neurotoxic actions. 6. None of the agonists or antagonists for any of the other major classes of glutamate receptors caused significant changes in Rb+ uptake. 7. We conclude that, even if a subpopulation of glutamate transporters in the rat cerebral cortex may be intimately linked to a fraction of Na+/K(+)-ATPase, it is not possible, under the present experimental conditions, to detect regulation of Na+/K(+)-ATPase by GluT.

Amino Acid Transport System X-AG↗
PubMed1985

Differences in L-[3H]glutamate accumulation and endogenous L-glutamate content in synaptic vesicles from mice selectively bred for differences in ethanol sensitivity.

The ATP-stimulated accumulation of L-[3H]glutamate by whole brain synaptic vesicle preparations from long-sleep and short-sleep mice, lines selectively bred for difference in sleep time response to acute ethanol administration, was examined. L-[3H]Glutamate accumulation in vesicles from short-sleep mice was approximately twice that observed in vesicles from long-sleep mice at three glutamate loading concentrations. The vesicular content of endogenous L-glutamate in crude and enriched vesicle preparations from short-sleep mice was approximately 1.5-fold higher than in vesicles from long-sleep mice. The data suggest that L-glutamate associated with synaptic vesicles may serve a role in glutamate neurosecretion.

Adenosine Triphosphate↗
PubMed1989

Glutamate metabolism of leukocytes and skin fibroblasts in spinocerebellar degeneration with lowered glutamate dehydrogenase activity.

From 21 patients with spinocerebellar degeneration 5 had markedly decreased glutamate dehydrogenase (GDH) activities and high values of serum plasma glutamate level after oral glutamate loading tests. Skin fibroblasts from patients with GHD deficiency showed intracellularly higher glutamate and lower glutathione contents than those from controls and showed significantly decreased viability in L-glutamate-containing medium. These data suggest that glutamate toxicity may at least play a part in this degeneration process.

Adolescent↗
PubMed1999

CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding.

Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current study, we examined the pharmacological profile and site of action of the non-amino-acid antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in intracellular calcium at human mGluR1b (hmGluR1b) with an apparent IC50 of 6.5 microM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 microM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill coefficient of glutamate. Similarly, CPCCOEt did not displace [3H]glutamate binding to membranes prepared from mGluR1a-expressing cells. To elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and Ala818, located at the extracellular surface of transmembrane segment VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818 at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 microM), i.e., a gain of function. These data suggest that CPCCOEt represents a novel class of G protein-coupled receptor antagonists inhibiting receptor signaling without affecting ligand binding. We propose that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.

Alanine↗
PubMedDate not supplied

Effect of neurosteroids on glutamate binding sites and glutamate uptake in rat hippocampus.

Effects of some neurosteroids on the binding of [3H]-glutamate, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]-MK-801, as well as on the [3H]-glutamate uptake were examined in rat hippocampus. The following compounds were evaluated: (a) positive modulators of the GABA(A) receptor: 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone), 5alpha-pregnane-3alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5alpha-pregnan-3alpha-ol-11,20-dione (alphaxalone) and 5alpha-androstan-3alpha-ol-17-one (androsterone); (b) compounds showing GABA(A)-antagonistic and/or N-methyl-D-aspartic acid (NMDA)-agonistic properties: dehydroepiandrosterone sulfate and pregnenolone sulfate; (c) a substance which, apart from its GABA(A)-agonistic potency, has a NMDA-antagonistic action: 5beta-pregnan-3alpha-ol-20-one. None of those neurosteroids tested at concentrations of 0.001-100 microM affected the binding of [3H]-glutamate, [3H]-AMPA and [3H]-MK-801 or the glutamate uptake. The present study suggests that the previously reported inhibitory effects of neurosteroids on excitatory amino acid-induced seizures and neurotoxicity can be linked neither to the direct interaction of these compounds with the above binding sites on glutamate receptor complexes, nor to the glutamate uptake mechanism.

Animals↗
PubMed2001

Inhibition of glutamate carboxypeptidase II by phosphonamidothionate derivatives of glutamic acid.

A limited series of N-thiophosphonyl-glutamates were found to be inhibitors of the prostate-specific membrane antigen (PSMA) form of glutamate carboxypeptidase II. Comparative inhibitory profiles of an analogous O-thiophosphonyl-2-hydroxyglutarate revealed that the amido-linkage of the N-thiophosphonyl-glutamate provides a significant enhancement of inhibitory potency presumably due to significant hydrogen-bonding interactions with acceptor groups in the active-site of PSMA resulting in tighter binding. An analogous N-phosphonyl-glutamate exhibited significantly greater inhibitory potency than the parent N-thiophosphonyl-glutamate indicating that the sulfur ligand of the N-thiophosphonyl-glutamates is responsible for less favorable active-site interactions than oxygen, potentially due to steric crowding from the longer P-S bond or as a result of active-site metal substitution of Co(II) for Zn(II) arising from assay conditions.

Antigens, Surface↗
PubMed1997

Activation of the metabotropic glutamate receptor mGluR5 prevents glutamate toxicity in primary cultures of cerebellar neurons.

1-Aminocyclopentane-trans-1,3-dicarboxylic acid, an agonist of the metabotropic glutamate receptors 1, 2, 3 and 5, prevents neurotoxicity of glutamate and of N-methyl-D-aspartate in primary cultures of cerebellar neurons. The aim of this work was to assess which of the metabotropic glutamate receptors (mGluRs) is responsible for the protective effect. We tested the protective effects of selective agonists for each type of receptor. It is shown that glutamate and N-methyl-D-aspartate neurotoxicity are prevented by the following compounds: 1-amino-cyclo-pentane-trans-1,3-dicarboxylic acid, agonist of mGluR1, 2, 3 and 5; 3,5-dihydroxyphenylglycine, agonist of mGluR1 and 5; S-4-carboxy-3-hydroxyphenylglycine, agonist of mGluR5 and antagonist of mGluR1; trans-azetidine-2,4-dicarboxylic acid, agonist of mGluR5. Glutamate neurotoxicity is not prevented by (2S,1'S,2'S)-2(2'-carboxycyclopropyl)glycine, an agonist of mGluR2 and mGluR3. Moreover, the protective effect of 1-aminocyclo-pentane-trans-1,3-dicarboxylic acid is prevented by alpha-methyl-4-carboxyphenylglycine, an antagonist of mGluR1 and 5, but not by alpha-methyl-4-tetrazoylphenylglycine, an antagonist of mGluR2 and 3. A protective effect of activation of mGluR1 can not be ruled out because of the limitations imposed by the lack of specificity of the agonists and antagonists currently available. The results shown clearly indicate that activation of mGluR5 prevents glutamate and N-methyl-D-aspartate neurotoxicity in primary cultures of cerebellar neurons.

Animals↗
PubMed2003

Glutamate spillover in the striatum depresses dopaminergic transmission by activating group I metabotropic glutamate receptors.

Cortical glutamate and substantia nigra dopamine (DA) afferents converge onto the dendritic spines of medium spiny neurons (MSNs) in the striatum where they act to modulate motor and cognitive functions. The released DA spills over from its synapse and is thought to regulate glutamatergic input by acting on distal DA receptors located on corticostriatal axon terminals. By monitoring evoked DA release directly using fast-scan cyclic voltammetry, we report a reciprocal modulation by glutamate spillover on evoked striatal DA release, induced by either glutamate uptake blockade or high-frequency stimulation of corticostriatal tracts. We demonstrate that this modulation is attributable to the activation of group I metabotropic glutamate receptors. Thus, under conditions in which glutamate escapes the confines of its synapse, it can elicit the presynaptic suppression of dopaminergic neurotransmission.

Amino Acid Transport System X-AG↗
PubMed1983

Oral glutamate loading in disorders with spinocerebellar and extrapyramidal involvement: effect on plasma glutamate, aspartate and taurine.

Altered metabolism of neuroexcitatory amino acids has been described in patients with a form of olivopontocerebellar atrophy (OPCA) associated with glutamate dehydrogenase (GDH) deficiency. To further investigate the specificity of these results, oral glutamate loading tests were performed in healthy controls, patients with GDH deficient OPCA as well as patients with non-GDH deficient degenerative disorders affecting primarily the function of the cerebellum and/or the basal ganglia. Following oral intake of monosodium glutamate, plasma levels of glutamate, aspartate and taurine increased significantly in controls and similar increases also occurred in patients with non-GDH deficient disorders. However, patients with GDH-deficient OPCA showed much greater elevations in plasma glutamate and aspartate and a rather flat taurine curve.

Aspartic Acid↗
PubMed1996

Inhibition of glutamate uptake induces progressive accumulation of extracellular glutamate and neuronal damage in rat cortical cultures.

It is known that neurons exposed to high concentrations of glutamate degenerate and die. The clearance of this amino acid from the extracellular space depends on their active transport by Na(+)-dependent high-affinity carriers. In the present study we tested whether inhibition of glutamate transport in mixed glial/neuronal cortical cultures induces accumulation of extracellular glutamate and whether such increase results in cell damage. Three inhibitors of glutamate transport were used: L-trans-pyrrolidine-2,4-dicarboxylate (PDC), DL-threo-beta-hydroxyaspartate (THA), and dihydrokainate (DHK). Cell damage was assessed by light microscopy observations, reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and leakage of lactate dehydrogenase. PDC induced a significant concentration- and time-dependent neuronal damage, whereas pure glial cultures were not affected. A good correlation was found between this damage and elevations of glutamate concentration in the medium. These effects of PDC were similar in glutamine-free medium and in medium supplemented with glutamine. THA induced identical cell damage and elevations of extracellular glutamate to those produced by PDC, while DHK did not affect at all any of these parameters. PDC- and THA-induced toxicity was protected by the N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate but not by the non-N-methyl-D-aspartate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline.

Animals↗
PubMed1996

Acute neurotoxicity of L-glutamate induced by impairment of the glutamate uptake system.

We examined the effect of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on the neurotoxicity of L-glutamate in organotypic cultures of rat spinal cord. Eighteen-day-old cultures were incubated with 500 microM L-glutamate, 1 mM PDC, or both. After 72 hours, the tissues were stained for acetylcholinesterase (AChE), and the ventral horn AChE-positive neurons (VHANs) analyzed using morphometry. Neither L-glutamate nor PDC affected AChE staining, but in combination they produced markedly reduced AChE staining in the dorsal horn and a significant decrease in the number of VHANs (especially the smaller VHANs) as compared with the control. Moreover, treatment with 200 microM PDC for 2 weeks preferentially affected the smaller VHANs. The neurotoxicity of L-glutamate plus PDC was blocked by the N-methyl-D-aspartate (NMDA) antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). Results suggest that glutamate uptake system has an important protective function in the aggravation of acute neuronal damage.

Acetylcholinesterase↗
PubMed1999

Changing patterns of spatial buffering of glutamate in developing rat retinae are mediated by the Müller cell glutamate transporter GLAST.

The patterns of expression of the glutamate transporter GLAST were compared with the patterns of uptake of exogenous D-aspartate, which is a substrate for all glutamate transporters. At postnatal day 0, fine radial processes and end feet of presumptive Müller cells were weakly immunoreactive for GLAST. At postnatal day 3, intense labelling was associated with astrocytes enveloping newly formed blood vessels on the vitread surface of the retina. Between postnatal days 7 and 10, there was a rapid increase in the intensity of labelling in the Müller cells but clear stratification of GLAST-immunoreactive processes in the inner plexiform layer was not observed until postnatal day 14. By comparison, D-aspartate uptake was initially associated with a wide variety of cellular elements including most neuroblasts, presumptive Müller cells, and astrocytes associated with blood vessels but was absent from the somata of many neurons in the ganglion cell layer and amacrine cell layer. There was a gradual contraction in the numbers of cells that were able to take up D-aspartate, such that, by adulthood, uptake was restricted mainly to Müller cells and astrocytes. We conclude that, during early retinal development, the low levels of GLAST expression by Müller cells permit D-aspartate, and by inference, glutamate, to permeate the retina freely, thus allowing uptake by other glutamate transporters on other cell types. As the retina matures, increased expression of GLAST by Müller cells restricts the access of D-aspartate to other cellular compartments in the retina. This changing pattern of spatial buffering of glutamate by GLAST probably has significant implications regarding our understanding of the role of glutamate during processes such as retinal synaptogenesis.

ATP-Binding Cassette Transporters↗
PubMed1996

Cellular expression of ionotropic glutamate receptor subunits on specific striatal neuron types and its implication for striatal vulnerability in glutamate receptor-mediated excitotoxicity.

Glutamate receptors are composed of subtype-specific subunits. Variation in the precise subunit composition of a receptor may result in significant functional differences. Thus, a precise knowledge of subunit composition on striatal neurons is a prerequisite for understanding the selective vulnerability of striatal neurons to excitatory amino acids. In the present study, we used an immunohistochemical double-labelling approach to localize ionotropic glutamate receptor subunits (NMDAR1, GluR1, GluR2/3, GluR4 and GluR5/6/7) on specific striatal neuron populations. Our results showed that striatal cholinergic and somatostatin interneurons were not labelled for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate, receptor subunits GluR1, GluR2/3 and GluR4. Most cholinergic and somatostatin interneurons (83.3% to 100%), however, were double-labelled for the N-methyl-D-aspartate receptor subunit NR1 and kainic acid receptor subunits GluR5/6/7. All parvalbumin interneurons were labelled for GluR1 and GluR4, and 96% GluR1 positive and 95% GluR4 positive neurons were also double-labelled as parvalbumin interneurons. About half of all parvalbumin interneurons co-localized with GluR2/3, and over 97% were labelled for NR1 and GluR5/6/7. Among striatal projection neurons, enkephalin-positive (mainly striatopallidal) neurons, striatonigral neurons (mainly substance P-positive) and calbindin-positive matrix neurons were not immunostained for GluR1 or GluR4. In contrast, 95% to 100% of each of these types of projection neurons were double-labelled for NR1, GluR2/3 and GluR5/6/7. Our results demonstrate that striatal neuron types differ in their expression of ionotropic glutamate receptor subunits and subtypes. The clear difference between striatal interneurons and projection neurons in ionotropic glutamate receptor subtypes/subunits supports the idea that differential glutamate receptor expression mechanism may account for the selective vulnerability of striatal projection neurons to excitotoxicity, and that glutamate receptor-mediated excitotoxicity may be involved in the striatal neurodegenerative diseases.

Animals↗
PubMed2004

Glutamate efflux from human cerebrocortical slices during ischemia: vesicular-like mode of glutamate release and sensitivity to A(2A) adenosine receptor blockade.

Glutamate extracellular accumulation is an early event in brain ischemia triggering excitotoxic neuron damage. We have investigated how to control the glutamate efflux from human cerebrocortical slices superfused in conditions simulating an acute ischemic insult (oxygen and glucose deprivation). The efflux of previously accumulated [3H]D-aspartate or endogenous glutamate increased starting 18 min after exposure to ischemia and returned almost to basal values in 6 min reperfusion with standard medium. Superfusion with Ca2+-free, EGTA (0.5 mM)-containing medium or with medium containing tetrodotoxin (TTX; 0.5 microM) inhibited the ischemia (24 min)-evoked [3H]D-aspartate efflux by about 50% and 65%, respectively. The ischemia (24 or 36 min)-evoked efflux of [3H]D-aspartate or endogenous glutamate was reduced at least 40% by the adenosine A(2A) receptor antagonist SCH 58261 (1 microM); the compound was effective when added up to 15 min after exposure to ischemia. No effect of SCH 58261 on the ischemia-evoked [3H]D-aspartate was found in Ca2+-free, EGTA-containing medium. To conclude, a significant component of the ischemia-evoked glutamate efflux in human cerebrocortical slices seems to occur by a vesicular-like mechanism. Endogenously released adenosine is likely to activate A(2A) receptors that enhance vesicular-like glutamate release during ischemia; A(2A) receptor antagonists would deserve consideration for their neuroprotective potential.

Adenosine A2 Receptor Antagonists↗