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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The time course of changes in extracellular glutamic acid levels and their Ca2+ dependency were studied in the rat striatum during focal cerebral ischaemia, using microdialysis. Ischaemia-induced changes were compared with those produced by high K(+)-evoked local depolarization. To optimize time resolution, glutamate was analysed continuously as the dialysate emerged from the microdialysis probe by either enzyme fluorimetry or biosensor. The Ca2+ dependency of glutamate changes was examined by perfusing the probe with Ca(2+)-free medium. With normal artificial CSF, ischaemia produced a biphasic increase in extracellular glutamate, which started from the onset of ischaemia. During the first phase lasting approximately 10 min, dialysate glutamate level increased from 5.8 +/- 0.9 microM.min-1 to 35.8 +/- 6.2 microM where it stabilized for approximately 3 min. During the second phase dialysate glutamate increased progressively to its maximum (82 +/- 8 microM), reached after 55 min of ischaemia, where it remained for as long as it was recorded (3 h). The overall changes in extracellular glutamate were similar when Ca2+ was omitted from the perfusion medium, except that the first phase was no longer detectable and, early in ischaemia, extracellular glutamate increased at a significantly slower rate than in the control group (2.2 +/- 1 microM.min-1; p < 0.05). On the basis of these data, we propose that most of the glutamate released in the extracellular space in severe ischaemia is of metabolic origin, probably originating from both neurons and glia, and caused by altered glutamate uptake mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular glutamate during focal cerebral ischaemia in rats: time course and calcium dependency. 791 20

Glutamic acid plays an important role as a main excitatory amino acid and also as one of the central metabolites in the central nervous system (CNS). This amino acid also acts as a toxic substance in the vertebrate CNS, including the retina, especially in ischemic conditions. This paper reviews recent advances in retinal research on glutamate metabolism and its relationship with pathogenesis of retinal diseases. Excessive administration of glutamate induces overstimulation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and influx of Na+, Cl-, and water to postsynaptic elements, causing lysis and swelling. In hypoxic or ischemic conditions, accumulation of glutamate was observed in most parts of the retina. Morphological and functional changes induced by ischemia could be prevented by preadministration of an antagonist of NMDA receptors. These results suggest that the same pathological mechanism as in the CNS exists in the retina. They also suggest that a new pharmacological approach for treating retinal abnormalities caused by ischemia could be introduced in the ophthalmology clinic in the near future. Abnormality of glutamate dehydrogenase, an important enzyme in the glutamate metabolism, has been reported in patients with spinocerebellar degenerations. Retinal dystrophy was also reported in some of them. Partial deficiency of heat-labile activity of this enzyme has been reported to be profoundly related with those patients with retinal abnormalities. This suggests that not only glutamate itself, but also abnormalities in its metabolic path way might be deeply correlated with the pathogenesis of retinal degeneration.
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PMID:[Dual nature of excitatory amino acids in the vertebrate retina]. 819 8

We investigated the disruption of spatial cognition due to transient forebrain ischemia using an 8-arm radial arm maze task in rats. Five or 10 min of ischemia did not affect the task acquisition. When rats established spatial cognition by daily training of the task, 10 min of ischemia significantly decreased the number of correct choices and increased the errors in the task when performed 24 h after reperfusion. These changes, however, returned to the normal level after about 4 days of daily training. Glutamic acid (Glu) and acetylcholine (ACh) release from the dorsal hippocampus (DH) was observed to transiently increase during ischemia. However, neither the content of noradrenaline (NA) nor the release of NA in the DH changed during ischemia. The NA and ACh release from the DH, however, gradually decreased during reperfusion, and the decrease became significant at 24 h after reperfusion. The NA content of the frontal cortex (FC) and the DH increased 7 days after reperfusion. These results suggest that the disruption of spatial cognition induced by 10 min of ischemia may be attributed to a greater degree to the dysfunction of the hippocampal ACh and NA, and cortical NA systems, rather than to the development of neuronal cell death in these areas.
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PMID:The disruption of spatial cognition and changes in brain amino acid, monoamine and acetylcholine in rats with transient cerebral ischemia. 883 52

The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.
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PMID:The pharmacology and mechanism of action of riluzole. 895 95

Amino acids, particularly glutamate, have been proposed to play an important role in the recovery of cardiac oxidative metabolism after ischemia. In this investigation, the metabolic and hemodynamic effects of glutamate infusion after coronary operations were studied. From 220 to 240 ml 0.1 mol/L l-glutamic acid solution was infused in 10 patients during 1 hour starting 2 hours after operation. A control group of 10 patients received an infusion of 240 ml saline solution. During glutamate infusion, there were significant increases in the uptake of glutamate (from 0.7 +/- 0.2 micromol/min in the basal state to a peak of 5.7 +/- 1.2 micromol/min at 20 minutes) and lactate (from 4.9 +/- 2.0 micromol/min in the basal state to 14.1 +/- 4.4 micromol/min at 60 minutes; p < 0.01), whereas the uptake and release of other substrates remained essentially unaffected. Arterial glutamate levels (in whole blood) increased from 103 +/- 10 micromol/L to 394 +/- 20 micromol/L at 60 minutes. Thirty minutes after discontinuation of the glutamate infusion, arterial levels had decreased to 129 +/- 17 micromol/L. The markedly improved utilization of lactate and the unchanged release of alanine together suggest that the oxidative metabolism of the heart was stimulated by glutamate. The metabolic changes were associated with improved myocardial performance. Left ventricular stroke work index increased from 26.8 +/- 2.1 gm x beat(-1) x m(-2) body surface area to 31.3 +/- 3.1 gm x beat(-1) x m(-2) body surface area during glutamate infusion. Metabolic support with amino acids may provide a means to improve recovery of metabolic and hemodynamic function of the heart early after cardiac operations.
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PMID:Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations. 897 38

L-Glutamic acid is a major excitatory neurotransmitter in the mammalian central nervous system. The termination of the glutamatergic transmission and the clearance of the excessive, neurotoxic concentrations of glutamate is ensured by a high affinity glutamate uptake system. Four homologous types of Na/K-dependent high affinity glutamate transporters, glutamate/aspartate transporter, glutamate transporter 1, excitatory amino acid carrier 1, and excitatory amino acid transporter 4, have recently been cloned and were assigned to a separate gene family, together with two neutral amino acid carriers, alanine/serine/cysteine transporter 1/serine/alanine/threonine transporter and adipocyte amino acid transporter. The genomic organization of these transporters is still under investigation. Very little is known about the nature of the factors and molecular mechanisms that regulate developmental, regional, and cell type-specific expression of the glutamate transporters and their aberrant functioning in neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and Alzheimer's disease). Some experimental conditions (e.g., ischemia, corticostriatal lesions, hyperosmolarity, culturing conditions) and several naturally occurring and synthetic compounds (e.g., glutamate receptor agonists, dopamine, alpha1- and beta-adrenergic agonists, cAMP, phorbol esters, arachidonic acid, nitric oxide, oxygen free radicals, amyloid beta-peptide, tumor necrosis factor-alpha, glucocorticosteroids, unidentified neuronal factors) affect the molecular expression and activity of glutamate transporters. Further elucidation of the molecular events that link epigenetic signals with transcriptional and post-transcriptional mechanisms (e.g., alternative splicing, translation and post-translational modifications) is crucial for the development of selective pharmacological tools and strategies interfering with the expression of the individual glutamate transporters.
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PMID:High affinity glutamate transporters: regulation of expression and activity. 922 6

To elucidate the role of astrocytes in the stress response of the central nervous system to ischemia, early gene expression was examined in rat cultured astrocytes after the exposure to hypoxia/reoxygenation, and we have previously cloned a novel RNA binding protein, RA301, from the reoxygenated astrocytes. Furthermore, we have now cloned a new gene for RA301 binding protein, termed YT521, by a yeast two-hybrid screening technique to explore RA301 functions. The YT521 cDNA is about 3200 bp long with an open reading frame encoding 712 amino acids. This amino acid sequence contains arginine-aspartic acid-glutamic acid rich region and glutamic acid rich one, and has a low degree of homology with RNA binding proteins such as U1-70k. Northern blot analysis revealed that YT521 mRNA expression was up-regulated in reoxygenated astrocytes. Induction of YT521 mRNA was mediated by endogenously generated reactive oxygen species, as it was suppressed by treatment of the cells with diphenyl iodonium which blocks oxygen-free radical formation by astrocytes. These expression patterns resembled those of RA301 mRNA. Far Western blot analysis showed that YT521 protein was not only interacting with RA301 protein, but also with SC35 and SF2, both of which are splicing factors. These results suggest that YT521 is a novel candidate for RNA splicing-related protein.
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PMID:Cloning of a gene, YT521, for a novel RNA splicing-related protein induced by hypoxia/reoxygenation. 947 74

Glutamate is an important substrate for the intermediary metabolism of the heart, particularly in association with ischemia. Early after coronary artery bypass surgery (CABG) myocardial uptake of glutamate seems to be limited by substrate availability (arterial levels). However, glutamate is not an innocuous substrate. As arterial levels of glutamate are important both for myocardial uptake and adverse effects, an attempt was made to determine a minimum dose of glutamate sufficient to supply the needs of the heart after CABG. Ten patients received and infusion of 220-240 ml of 0.1 M L-glutamic acid solution at varying rates during two 30-min periods, starting 2 h after uncomplicated elective CABG. Intravenous glutamate infusion caused a dose-dependent linear increase in arterial glutamate and an increased myocardial uptake of glutamate. However, myocardial uptake of glutamate correlated with arterial levels only at lower infusion rates. Although maximal peak uptake in individual patients (6.6 +/- 1.1 mumol/min) occurred at an average increase of arterial whole blood glutamate of 172 +/- 34 mumol/L, the greatest impact on myocardial glutamate uptake was achieved by increasing arterial whole blood glutamate by less than 100 mumol/L. This implies that an infusion rate of 30-40 mg glutamate/kg BW/h could suffice to achieve a maximal or near maximal myocardial glutamate uptake in most patients after CABG. The adequacy of this dosage remains to be confirmed in high-risk patients.
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PMID:Assessment of myocardial glutamate requirements early after coronary artery bypass surgery. 976 29

Glutamate transport across the plasma membrane of neurons and glia is powered by the transmembrane electrochemical gradients for sodium, potassium, and pH, but there is controversy over the number of Na+ cotransported with glutamate. The stoichiometry of glutamate transporters is important because it determines a lower limit to the extracellular glutamate concentration, [glu]o, in both normal and pathological conditions. We used whole-cell clamping to study the stoichiometry of the glial transporter GLT-1, the most abundant glutamate transporter in the brain, expressed under control of the Tet-On system in a Chinese hamster ovary (CHO) cell line selected for low endogenous glutamate transport. After the induction of GLT-1 expression with doxycycline, glutamate evoked a Na+-dependent inward current with the voltage dependence and pharmacology of GLT-1 and acidified the cell cytoplasm. Raising [K+]o around cells clamped with electrodes containing sodium and glutamate evoked an outward reversed uptake current. These responses were reduced by the specific GLT-1 blocker dihydrokainate (DHK). DHK evoked an outward current with NO3-, but not with Cl-, as the main intracellular anion, suggesting that the anion conductance of the transporter is active even without external glutamate but generates little current in the absence of highly permeable anions like NO3-. Measuring the reversal potential of the transporter current in various ionic conditions suggested that the transport of one glutamate anion is coupled to the cotransport of three Na+ and one H+ and to the countertransport of one K+. This suggests that in ischemia, when [K+]o rises to 60 mM, the reversal of glutamate transporters will raise [glu]o to >50 microM.
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PMID:Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. 982 23

Dyskinesia is frequently seen in neurological disorders affecting the basal ganglia. Iminodipropionitrile (IDPN) produces a somewhat similar motor syndrome in rodents, one that is a possible model for dyskinesia. Because in previous studies the compound (N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3 pyridine-carboximidoyl-chloride) (Bimoclomol, BRLP-42) was shown to provide protection against IDPN-induced retinopathy; we investigated the effect of BRLP-42 on IDPN-induced motor changes and on IDPN-induced cerebral amino acid level changes in rats and mice. IDPN had a biphasic effect on motor activity in C57BL/6 mice: it was a depressant for 24 days and a stimulant after 30 days. Bimoclomol inhibited the motor depressant effect and enhanced the stimulatory effect of IDPN in this mouse strain. In BALB/cBy mice and Sprague Dawley rats IDPN produced persistent vertical head movements and changes in the level of glutamic acid in brain. Bimoclomol reduced the effect of IDPN on head movements and blocked the effect on cerebral glutamate; by itself it had no effect on motor activity in either species. Bimoclomol inhibited ischemia-induced [3H]norepinephrine release from rat hippocampal slices. Our findings indicate that Bimoclomol could have a beneficial effect on some dyskinesias, and on drug-induced vertical head movements.
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PMID:Effect of bimoclomol (N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3 pyridine-carboximidoyl-chloride) on iminodipropionitrile-induced central effects. 1009 20


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