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

Although the cerebroprotective effects of hypothermia in focal models of ischemia are undisputed, the underlying mechanisms of this protection are still subject to much controversy. To analyze whether mild hypothermia attenuates glutamate levels in the penumbra surrounding permanent focal infarcts, extracellular glutamate concentration was analyzed bilaterally by microdialysis 20 minutes before to 120 minutes after a middle cerebral artery occlusion (MCAO) in rats. Normothermic animals (n = 11) had a baseline glutamate concentration of 1.14 +/- 0.40 mumol/ml (standard error of the mean) before the MCAO. Extracellular glutamate levels increased gradually after vessel occlusion to peak at 10.1 +/- 1.45 mumol/ml 80 minutes after the MCAO. This level gradually decreased to 5.72 +/- 1.67 mumol/ml by 120 minutes. Hypothermic animals (n = 11) had a baseline glutamate concentration of 1.73 +/- 0.83 mumol/ml before the MCAO. Extracellular glutamate levels increased after vessel occlusion but stabilized at 3.47 +/- 1.37 mumol/ml 30 minutes after the MCAO and remained stable until completion of the experiment. There were no significant differences in cortical blood flow between the normothermic and hypothermic groups at any time during the experiment. Infarct volumes, expressed as a percentage of the volume of the right (ipsilateral) hemisphere, were 19.8 +/- 2.16% in the normothermic group and 13.0 +/- 1.42% in the hypothermic group (P < 0.02). Although the normothermic penumbral glutamate levels began to increase immediately after the MCAO, they did not peak until 80 minutes after occlusion. In contrast, the normothermic core glutamate levels peaked within 30 minutes after the MCAO. Glutamate diffusion from the core region to the penumbra might account for this delay. Hypothermic cerebroprotection might involve a reduction in the pool of potentially diffusable glutamate in the core region but have little direct effect on glutamate release in the penumbra.
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PMID:Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. 872 54

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78

Glutamate is one of the principal neurotoxins in the pathogenesis of ischemic neuronal injury. Elevated glutamate levels in ischemia have been well documented in many animal stroke models. Recent work in humans also shows a similar trend. We have used our acute focal ischemic model of the human brain to study the response of glutamate levels by in vivo microdialysis during ischemia using two different perfusates. The addition of 30 mM of glucose to the perfusate attenuated the percentages of dialysate glutamate levels from 4.27 +/- 1.7 to 1.34 +/- 0.47 (P < 0.001) during partial ischemia and from 21.42 +/- 6.05 to 7.25 +/- 1.43 (P < 0.05) with total ischemia. The pre-ischemic values of glutamate were similar with the two perfusates. These results indicate that the ischemia-induced rise in glutamate is attenuated by exogenous glucose delivery in the human stroke model.
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PMID:Glucose-induced decrease in glutamate levels in ischemic human brain by in-vivo microdialysis. 873 47

Glutamate receptors are numerous on the ischemia vulnerable CA-1 pyramidal cells. Postischemic use of the AMPA antagonist NBQX has shown up to 80% protection against cell death. Three aspects of this were studied: In the first study, male Wistar rats were given NBQX (30 mg/kg x 3) either 20 hours or immediately (0 h) before 12 min of 4-vessel occlusion with hypotension. After six days of reperfusion comparison with an untreated group showed almost full protection in the 0 h group (4% cell loss, p < 0.001) but only slight protection in the 20 h group (62% cell loss, p < 0.05). After 12 min of ischemia in the present model, eosinophilic CA-1 cells are seen from day 2 on. Since there could be a late, deleterious calcium influx via NMDA receptors, one group of ischemic rats was given MK-801 (5 mg/kg i.p.) 24 hours after ischemia. However, quantitation 6 days later of remaining CA-1 cells showed no protection. In the third study referred here, two groups of ischemic rats were given NBQX (30 mg/kg x 3) immediately after ischemia. The groups survive for six and 21 days, respectively. Counting of CA-1 pyramidal cells showed an equal, significant protection in both groups (approx 20% cell loss).
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PMID:Extended studies on the effect of glutamate antagonists on ischemic CA-1 damage. 878 Aug 1

Glutamate (Glu) neurotoxicity is an important element of a number of neurological disorders including central nervous system (CNS) ischemia. We evaluated the effects of the novel AMPA Glu antagonist LY293558 on functional neurological outcome in two rabbit stroke models. In the reversible spinal cord ischemia model, ischemia of the caudal lumbar spinal cord was produced by temporary occlusion of the abdominal aorta. LY293558 was administered 5 min after recirculation as a 16 mg/kg i.v. bolus followed by 2.2 mg/kg infused over 1 h. Control animals received saline. LY293558 significantly increased the duration of ischemia required to produce paraplegia, from 30.5 +/- 15.8 min (mean +/- SD) controls to 50.1 +/- 11.5 in treated animals (p < 0.01). In an irreversible model of cerebral ischemia, 50 microns plastic microspheres were injected into the carotid artery and lodged in the cerebral microvasculature. LY293558 did not significantly reduce neurological damage in this model. These data suggest that LY293558 may have therapeutic benefit following some types of ischemic injury.
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PMID:The AMPA antagonist LY293558 improves functional neurological outcome following reversible spinal cord ischemia in rabbits. 878 41

An apparent transient increase in local glucose utilization has been demonstrated in certain brain areas after global and focal ischemia in several models. A coincident transient increase in extracellular glutamate has been shown in the same brain regions in many of these models. To test the hypothesis that an increase in metabolism is an important component of the excitotoxic effect of glutamate, we perfused glutamate at different concentrations (0.01, 0.1, 0.5, 1 M) into the extracellular space, and performed 2-deoxyglucose autoradiography after 90 min of infusion. Furthermore, we infused 14C-labeled glutamate to investigate its diffusion characteristics within the brain using autoradiographic methods. Glutamate at 0.5 and 1 M concentration caused large consistent areas of brain damage with all the histological features of acute infarction, although ischemia does not occur in this model. Glucose utilization was significantly increased (115 +/- 20 vs. 56 +/- 13 mumol/100 g/min in controls p < 0.01) in a sharply demarcated concentric zone, at the boundary between histologically damaged and normal brain, suggesting that viable cells not yet destroyed by glutamate respond by increased glucose metabolism. [14C] Glutamate diffused into the brain in a dose-dependent manner, and the pattern of its diffusion corresponded closely to that of the histological lesion and the zone of increased glucose uptake. We speculate that the increase in glucose use, which is not caused by ischemia in this model, is due to a metabolic response to glutamate and may be due to attempts to restore ionic homeostasis or repair cell damage.
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PMID:Patterns of increased glucose use following extracellular infusion of glutamate: an autoradiographic study. 879 74

This study was designed to evaluate the ability of dexmedetomidine, an alpha 2-adrenergic agonist, to attenuate increases in the hippocampal concentration of extracellular glutamate and glycine that result from episodes of transient global cerebral ischemia. After the induction of anesthesia with halothane and oxygen, microdialysis catheters were stereotactically inserted into the hippocampi of 16 New Zealand white rabbits. After the collection of baseline samples of dialysate, animals were randomly assigned to receive an intravenous infusion of either saline (n = 8) or dexmedetomidine (n = 8). Transient global cerebral ischemia was produced by the inflation of a neck tourniquet and induction of deliberate hypotension for 10 min. Dialysates were collected during the ischemic period and for the ensuing 60 min of reperfusion. During ischemia, the concentrations of glutamate and glycine increased from the preischemic baseline in both groups. Glutamate concentrations rapidly returned to baseline after reperfusion, whereas glycine concentrations remained elevated throughout the reperfusion period. There were no significant differences between the control and dexmedetomidine-treated groups. These results suggest that the mechanism of the putative neuroprotective effects of dexmedetomidine is not related to decreased concentrations of glutamate or glycine.
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PMID:Dexmedetomidine does not attenuate increases in excitatory amino acids after transient global ischemia in the rabbit. 880 36

Glutamate has been proposed to play a critical role in acute ischemic pathophysiology in the brain. In this study, glutamate was monitored by the dialysis electrode technique, in which glutamate is oxidized by glutamate oxidase producing hydrogen peroxide which is then amperometrically detected on a platinum electrode set at +650 mV vs Ag/AgCl. A dialysis electrode, which consists of a microdialysis probe with a built-in platinum electrode, provides a continuous glutamate oxidase perfusion inside of the probe. Perfusion with this solution allows real-time monitoring of glutamate dynamics in the extracellular space during ischemia. This study was designed to collect detailed information on rapid changes in the extracellular glutamate concentration of the rat striatum and demonstrated two distinct phases of glutamate release during early severe brain ischemia.
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PMID:Real time monitoring of biphasic glutamate release using dialysis electrode in rat acute brain ischemia. 880 58

The distribution of the AMPA, kainate and NMDA glutamate receptor subunit proteins GluR2(4), GluR5/6/7 and NMDAR1, respectively, were analyzed in the dog hippocampus and neocortex and compared to macaque monkeys and humans. In the dog hippocampus, these glutamate receptor classes exhibited a comparable distribution with few differences in densities of labeled of neurons in the CA1-CA3 fields and in neuropil staining patterns in the dentate gyrus. In particular, the GluR5/6/7 subunit proteins were characterized by a more restricted cellular distribution in the CA1-CA3 fields. In the dog neocortex, the GluR2(4) subunit was found in a higher number of neurons in layers III and V compared to the GluR5/6/7 or NMDAR1 subunits, which were found predominantly in a population of medium-to-large layer V pyramidal neurons. Layers II and VI were consistently densely labeled with all three receptor classes, especially in the case of the GluR5/6/7 and NMDAR1 subunits. All three antibodies used thus far showed an intense labeling of the perikaryon and dendritic segments in the dog cerebral cortex. Apical dendrites could be followed through several layers in some cases, and formed well-stained plexuses in all of the neocortical layers. These patterns were very similar to those observed in the hippocampus and neocortex of both monkey and human, although GluR2(4) and NMDAR1 immunoreactivity was visualized in more heterogeneous populations of cortical neurons in the primates than in dogs. Glutamate is the principal excitatory neurotransmitter in the brain and is involved in the excitotoxic mechanisms occurring in pathologic conditions such as epilepsy and cerebral ischemia. The dog has been shown to represent a reliable large animal model for several neurologic disorders and is used particularly in investigations of the cerebral repercussions of cardiac arrest. The overall similarity of the staining patterns in dogs and primates observed in the present study suggest that the dog model may be highly valuable for the characterization of potential cellular and synaptic shifts in the distribution and expression of specific glutamate receptor subunits, in the context of other biochemical and morphologic effects of global brain ischemia and reperfusion following cardiac arrest.
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PMID:Distribution of glutamate receptor subunit proteins GluR2(4), GluR5/6/7, and NMDAR1 in the canine and primate cerebral cortex: a comparative immunohistochemical analysis. 881 84

Glutamate induced neurotoxicity has been proposed to account for the loss of neurons after ischemia as well as in the cause of neurodegenerative diseases. We have studied the effects of exogenous glutamate on survival of neurons from chick embryo telencephalon, precultured with a peptide derivative for 8 days. The peptide derivative Cerebrolysin is a drug produced by standardised enzymatic breakdown consisting of 80% peptides and 20% amino acids. Toxic effects of acute glutamate exposure were prevented by Cerebrolysin in a concentration-dependent manner. 20 and 40 microliters Cerebrolysin produce distinct neuroprotective effects. However, 80 microliters Cerebrolysin/ml nutrition medium more than doubles neuronal viability compared to untreated control cells. These concentration-dependent effects of Cerebrolysin were evident even at the light microscopic level.
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PMID:Death of cultured telencephalon neurons induced by glutamate is reduced by the peptide derivative Cerebrolysin. 884 72


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