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

Glutamate antagonists are the most powerful neuroprotective drugs in laboratory studies of focal cerebral ischemia. Because the majority of clinical conditions in which focal brain ischemia occurs are associated with high intracranial pressure (ICP), we have used the rat acute subdural hematoma model to evaluate the effects of three glutamate N-methyl-D-aspartate antagonists, MK-801, CGS 19755 (SELFOTEL), D-CPP-ene, and mannitol, upon ICP and also upon the volume of ischemic brain damage. Only mannitol produced a significant reduction in ICP and improved cerebral perfusion pressure. The three glutamate antagonists did not significantly affect ICP or cerebral perfusion pressure, but they were associated with a significantly smaller zone of focal brain damage, when compared to the mannitol and saline groups. N-methyl-D-aspartate antagonists do not increase ICP or jeopardize cerebral perfusion pressure when administered under anesthesia with a controlled PaCO2 level. Further studies in humans are indicated.
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PMID:Effect of neuroprotective N-methyl-D-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model. 793 30

Glutamate is the principal excitatory neurotransmitter in the brain and, as such, it inevitably plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. The process of "kindling" limbic seizures in rodents by repeated electrical stimulation is dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The function of these receptors is enhanced in the hippocampus of kindled rats and in the cerebral cortex of patients with focal epilepsy. Microdialysis studies show an increase in the extracellular concentration of glutamate and aspartate before or during seizure onset, suggesting that either enhanced amino acid release or impaired uptake contributes to seizure initiation. Glutamate antagonists selective for NMDA or non-NMDA receptors are potent anticonvulsants when given systemically in a wide variety of animal models of epilepsy. They are of limited efficacy against kindled seizures in rats and (on the basis of preliminary evidence) in patients with drug-refractory complex partial seizures. Cognitive side effects appear to be a significant problem with competitive, as well as noncompetitive, NMDA antagonists. Glutamate receptor antagonists provide significant protection against brain damage following global or focal cerebral ischemia or acute traumatic injury in rodent models. Anticonvulsant compounds of the lamotrigine type, which act on sodium channels and reduce ischemia-induced glutamate release, are cerebroprotective in rodent ischemia models and are free from the cognitive side effects of NMDA-receptor antagonists.
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PMID:The role of glutamate in epilepsy and other CNS disorders. 797 2

Stroke remains the third leading cause of death in this country, although recent advances in both clinical and basic science research have revolutionized the concept of stroke. Studies of primary and secondary stroke prevention have now documented the means to prevent thousands of cases of stroke each year. Three distinct strategies are evolving for intervention in the acute stroke process. Evidence is clear that ischemia leads to a toxic accumulation of intracellular calcium, in part mediated by excitatory neurotransmitters such as glutamate. Glutamate antagonists have shown clear benefit in experimental stroke models, and early clinical trials are underway. Acute revascularization to restore perfusion is also feasible and may minimize the extent of infarction. Studies of fibrinolytic agents are promising, with randomized clinical studies being done. While reperfusion is desired, it may be associated with additional neuronal injury. The development of anaerobic metabolism followed by reperfusion and aerobic conditions favors oxidation and free-radical formation. This mechanism of injury can be decreased by agents known to scavenge free radicals, and clinical trials are also testing this. This revolution in the understanding of ischemia, as well as the outpouring of new pharmacologic agents, is making stroke a true neurologic emergency requiring immediate intervention.
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PMID:Stroke. Revolution in therapy. 797 68

Using microdialysis, we investigated the effect of hyperthermia on glutamate release in penumbral cortex of rats with 2 h of either normothermic (37 degrees C) or hyperthermic (39 degrees C) middle cerebral artery (MCA) occlusion. Penumbral blood flow (CBF) was measured by laser-Doppler flowmetry. CBF values (expressed as % preischemic values) in normothermic and hyperthermic groups were 24 +/- 11 (SD) and 24 +/- 16%, respectively, during ischemia and 102 +/- 81 and 147 +/- 79% during recirculation. Average extracellular glutamate in the hyperthermic group increased from a baseline of 7 +/- 2 microM to a peak of 217 +/- 184 microM at 10-20 min after onset of ischemia but returned to near baseline after 60 min. Glutamate in the normothermic group increased from 4 +/- 2 microM to a peak of 26 +/- 17 microM at 10-20 min after MCA occlusion but fell to near-baseline before recirculation. Thus reuptake systems appeared to remain functional in ischemic penumbra, even during hyperthermia. Ischemic glutamate release was significantly higher in hyperthermic than in normothermic rats: average values of individual rats' peak levels were 251 +/- 221 microM and 37 +/- 34 microM, respectively. The ischemic CBF threshold value for glutamate release was 33% of control in the normothermic group but 61% in the hyperthermic group.
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PMID:Effect of hyperthermia on glutamate release in ischemic penumbra after middle cerebral artery occlusion in rats. 797 7

Glutamate is the primary excitatory amino acid in the mammalian central nervous system. Normal excitation of glutamate receptors initiates the stimulation of phospholipases and lipases with the generation of second messengers that are necessary for normal cell function. The overstimulation of glutamate receptors can initiate a cascade of biochemical events including stimulation of membrane phospholipid turnover, excessive calcium entry, abnormal phosphorylation, and proteolysis. These events may be responsible for neuronal injury and degeneration found in Alzheimer disease, ischemia, spinal cord trauma, epilepsy, and Huntington disease.
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PMID:Involvement of glutamate receptors, lipases, and phospholipases in long-term potentiation and neurodegeneration. 805 91

Enhancement of myocardial recovery with glutamate-enriched cold blood potassium cardioplegia (BPC) was evaluated using an isolated working heart model. Three groups of hearts from immature rabbits were subjected to 20 minutes of warm (37 degrees C) ischemia to allow energy depletion, followed by 90 minutes of hypothermic (10 degrees C) ischemia. Myocardial protection provided during hypothermia consisted of cardioplegia infusion, at 50 mm Hg every 30 minutes at 4 degrees C, of either St. Thomas' Hospital solution (group 1, n = 6), oxygenated BPC (group 2, n = 7), or oxygenated BPC enriched with 20 mmol/L L-glutamate (group 3, n = 7). Percent recovery of aortic flow was 87.6% +/- 6.3% (results expressed as mean +/- standard error of the mean) in group 3, which was significantly better than for either group 1 (63.4% +/- 4.0%) or group 2 (47.0% +/- 3.5%) (p < 0.05 by analysis of variance). Group 3 hearts had significantly better recovery of myocardial energy stores (mumol/g dry weight) compared with group 1 or 2 hearts: adenosine triphosphate, 17.8 +/- 1.1 versus 12.4 +/- 1.5 and 12.1 +/- 0.4; creatine phosphate, 25.9 +/- 1.8 versus 17.8 +/- 1.8 and 20.3 +/- 0.7; and glycogen, 140.7 +/- 12.6 versus 98.7 +/- 9.9 and 60.7 +/- 9.9 (p < 0.05). Glutamate-enriched BPC provided excellent myocardial protection after ischemia in this immature model, and this study quantitatively supports the use of glutamate-enriched BPC in neonatal clinical practice.
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PMID:Improved recovery of immature myocardium with L-glutamate blood cardioplegia. 809 34

Polyamines positively modulate the activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors. The concentration of polyamines in the brain increases in certain pathological conditions, such as ischemia and brain trauma, and these compounds have been postulated to play a role in excitotoxic neuronal death. In primary cultures of rat cerebellar granule neurons, exogenous application of the polyamines spermidine and spermine (but not putrescine) potentiated the delayed neurotoxicity elicited by NMDA receptor stimulation with glutamate. Furthermore, both toxic and nontoxic concentrations of glutamate stimulated the activity of ornithine decarboxylase (ODC)--the key regulatory enzyme in polyamine synthesis--and increased the concentration of ODC mRNA in cerebellar granule neurons but not in glial cells. Glutamate-induced ODC activation but not neurotoxicity was blocked by the ODC inhibitor difluoromethylornithine. Thus, high extracellular polyamine concentrations potentiate glutamate-triggered neuronal death, but the glutamate-induced increase in neuronal ODC activity may not play a determinant role in the cascade of intracellular events responsible for delayed excitotoxicity.
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PMID:Induction of ornithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons. 809 73

Periventricular white matter injury, the principal variety of brain injury of the human premature infant, involves differentiating oligodendroglia. Nothing is known of the biochemical mechanism of oligodendroglial death in this disorder. Because an early event in periventricular white matter injury is ischemia-induced axonal disruption and because such axonal destruction could lead to a marked increase in local concentrations of glutamate, we evaluated the vulnerability of differentiating oligodendroglia to glutamate in a culture model. Oligodendroglia were isolated from mixed-glial primary cultures by a selective detachment technique and grown in a primary culture under conditions that lead to differentiation. These oligodendroglia were found to be highly vulnerable to glutamate-induced cell death. The EC50 for glutamate for a 24 hr exposure was approximately 200 microM, comparable to the value reported for neurons in conventional cerebral cortical cultures. Astrocytes, in contrast, were shown to be resistant to as much as 5 mM glutamate. Study of glutamate receptor antagonists and glutamate transport substrates showed that the glutamate-induced oligodendroglial death was not related to a receptor mechanism, as operates in neurons, but rather was secondary to glutamate uptake by the oligodendroglia. Glutamate transport by high-affinity, sodium-dependent and by sodium-independent systems was shown. The central importance of glutamate uptake for the toxic effect of glutamate was shown by total prevention of the oligodendroglial toxicity by the simultaneous inhibition of glutamate uptake by the specific inhibitor D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the toxicity of glutamate was mediated by free radical attack, the consequence of glutathione depletion, apparently caused by the action of a glutamate-cystine exchange mechanism that results in cystine and thereby glutathione depletion. Thus, addition of cystine or cysteine totally prevented the glutamate toxicity to oligodendroglia. Second, glutamate exposure led to cystine efflux. Third, glutathione levels decreased markedly in cells exposed to glutamate, and this marked decrease preceded the loss of cell viability. Fourth, glutamate toxicity could be prevented totally by exposure to different free radical scavengers, vitamin E and idebenone. The data thus show that glutamate is highly toxic to oligodendroglia. Moreover, the findings raise the possibilities that such glutamate toxicity is operative in the oligodendroglial cell death associated with ischemic processes that disrupt axons, such as periventricular white matter injury of the premature infant, and that novel therapies directed against glutamate transport, glutathione depletion, and free radical attack might be beneficial in prevention of that injury.
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PMID:Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. 809 41

The time-course of changes in extracellular glutamate and energy metabolism during 30 or 60 min of complete cerebral ischemia and 60-90 min of reperfusion was investigated by microdialysis and magnetic resonance spectroscopy in parallel groups of rats. During the first 10 min of ischemia, adenosine triphosphate (ATP) was completely depleted, and lactate increased 10-fold; after 30 min, intracellular pH had decreased to 6.33 +/- 0.11. ATP and lactate did not change further between 30 and 60 min of ischemia. Glutamate increased 30-fold between 10 and 30 min of ischemia and continued to increase in the 60-min ischemia group. After 30 min of reperfusion, glutamate had returned to pre-ischemic levels in both groups. The cellular energy state recovered within 50-60 min after 30 min of ischemia but never returned to more than 60% of baseline values after 60 min of ischemia. The continued increase in extracellular glutamate after total depletion of ATP suggests that glutamate release during ischemia is not entirely energy dependent. Ca(2+)-independent glutamate release and failure of energy-dependent glutamate re-uptake mechanisms may result in continued increase in extracellular glutamate. The rapid normalization of extracellular glutamate after 30 and 60 min of ischemia despite differences in the recovery of energy metabolism suggests that the glutamate levels were reduced by an energy-independent mechanism, such as diffusion into the restored circulation.
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PMID:Relationship between extracellular neurotransmitter amino acids and energy metabolism during cerebral ischemia in rats monitored by microdialysis and in vivo magnetic resonance spectroscopy. 809 89

The neurons in the hippocampus, striatum, and cerebral or cerebellar cortex are particularly vulnerable to a short period of ischemia. Following brief ischemic insult, neurons die after a latent period for a few days (delayed neuronal death). To account for this selective vulnerability to ischemia, glutamate-calcium hypothesis has come to be widely accepted. Glutamate, a major excitatory neurotransmitter, increases during ischemia. The hypothesis proposes that accumulated extracellular glutamate in turn triggers an increase of intracellular Ca2+ and eventually neuronal cell death. When neurons are subjected to sublethal ischemia, they express stress response and become transiently tolerant to further ischemia. These characteristics of ischemic neuronal death following brief ischemia indicate that neuronal death under such situation is not due to simple destruction of the cell. On the contrary, the fate of neurons following ischemia seems to depend on the basic cellular function which determines death or survival. This assumption is partially supported by the fact that some neurotrophic factors can save neurons following ischemic. However, the further basic mechanism of ischemic neuronal cell death is still unknown.
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PMID:[Cerebral ischemia and neuronal death]. 813 85


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