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

Cerebral artery occlusion produces regions of incomplete ischemia (the ischemic penumbra), which, in the absence of reflow, undergo progressive metabolic deterioration culminating in infarction. The factors causing infarction are not yet established, but progression to cell death is preceded by progressive acidosis, decreasing glucose utilization, and ATP depletion. To identify potential mechanisms of glial death in the ischemic penumbra, astrocytes in culture were subjected to conditions that occur during incomplete ischemia: hypoxia, acidosis, and raised extracellular K+. Neither acidosis (to pH 6.2) nor chemical hypoxia (5 mM azide) alone produced significant astrocyte death or marked ATP depletion. By contrast, hypoxia combined with acidosis caused near-complete ATP depletion by 3.5 h and 70% cell death after 7 h. Glycolytic rate increased during hypoxia alone but decreased during hypoxia with acidosis. Since glycolysis is the sole source of ATP production during hypoxia, acidosis inhibition of glycolysis is a likely cause of the far greater ATP depletion resulting from hypoxia with acidosis. Glutamate uptake was reduced during hypoxia and further reduced during hypoxia with acidosis, consistent with the changes in astrocyte ATP. Glutamate uptake, ATP levels, and glycolytic rate each exhibited reductions that were progressive over 3 h of hypoxia with acidosis, and these changes were accompanied by progressive intracellular acidosis. Since ATP depletion leads to acidosis, and acidosis inhibits glycolysis, these findings suggest a regenerative cycle initiated by the combination of hypoxia with acidosis. This cycle could result in progressive metabolic decline and cell death in the ischemic penumbra.
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PMID:Astrocyte energetics, function, and death under conditions of incomplete ischemia: a mechanism of glial death in the penumbra. 929 57

Glutamate, the major excitatory neurotransmitter in the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). We tested the hypothesis that excessive exposure to glutamate, or related agonists, produces neurotoxicity in enteric neurons. Prolonged stimulation of enteric ganglia by glutamate caused necrosis and apoptosis in enteric neurons. Acute and delayed cell deaths were observed. Glutamate neurotoxicity was mimicked by NMDA and blocked by the NMDA antagonist D-2-amino-5-phosphonopentanoate. Excitotoxicity was more pronounced in cultured enteric ganglia than in intact preparations of bowel, presumably because of a reduction in glutamate uptake. Glutamate-immunoreactive neurons were found in cultured myenteric ganglia, and a subset of enteric neurons expressed NMDA (NR1, NR2A/B), AMPA (GluR1, GluR2/3), and kainate (GluR5/6/7) receptor subunits. Glutamate receptors were clustered on enteric neurites. Stimulation of cultured enteric neurons by kainic acid led to the swelling of somas and the growth of varicosities ("blebs") on neurites. Blebs formed close to neurite intersections and were enriched in mitochondria, as revealed by rhodamine 123 staining. Kainic acid also produced a loss of mitochondrial membrane potential in cultured enteric neurons at sites where blebs tended to form. These observations demonstrate, for the first time, excitotoxicity in the ENS and suggest that overactivation of enteric glutamate receptors may contribute to the intestinal damage produced by anoxia, ischemia, and excitotoxins present in food.
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PMID:Excitotoxicity in the enteric nervous system. 934 49

Glutamate (Glu) plays an important role in the early development of brain injuries caused by ischemia, i.e. stroke, or brain trauma. Glu induces a rapid astroglial swelling which, in turn, deranges the composition of neuroactive substances in the extracellular space. We report that Glu can induce astroglial cell swelling by interaction with metabotropic Glu receptors (mGluRs). Furthermore, the Na(+)-K(+)-2Cl- cotransporter, a Na(+)-K(+) ATPase, and the Na(+)-dependent electrogenic Glu carrier seem to be involved in this Glu-induced astroglial cell swelling. Two methods for studying cell swelling arc described. One is based on variations in the signal emitted by the fluorescent probe fura-2/AM when excited at its isosbestic point. These variations were shown to be directly proportional to variations in intracellular volume. Relative changes in cell volume and intracellular calcium concentration could be detected simultaneously in single astroglial cells. The other method used permits the cell volume to be calculated in relative terms with the aid of image processing techniques.
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PMID:Glutamate induced astroglial swelling--methods and mechanisms. 941 5

Loss of retinal ganglion cells (RGCs) is a hallmark of many ophthalmic diseases including glaucoma, retinal ischemia due to central artery occlusion, anterior ischemic optic neuropathy and may be significant in optic neuritis, optic nerve trauma, and AIDS. Recent research indicates that neurotoxicity is caused by excessive stimulation of receptors for excitatory amino acids (EAAs). In particular, the amino acid glutamate has been shown to act as a neurotoxin which exerts its toxic effect on RGCs predominantly through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. NMDA-receptor-mediated toxicity in RGCs is dependent on the influx of extracellular Ca2+. The increase in [Ca2+]i acts as a second messenger that sets in motion the cascade leading to eventual cell death. Glutamate stimulates its own release in a positive feedback loop by its interaction with the non-NMDA receptor subtypes. Ca(2+)-induced Ca2+ release and further influx of Ca2+ through voltage-gated Ca2+ channels after glutamate-induced depolarization contribute to glutamate toxicity. In vitro and in vivo studies suggest that the use of selective NMDA receptor antagonists or Ca2+ channel blockers should be useful in preventing or at least abating neuronal loss in the retina. Of particular importance for future clinical use of NMDA receptor antagonists in the treatment of acute vascular insults is the finding that some drugs can prevent glutamate-induced neurotoxicity, even when administered a few hours after the onset of retinal ischemia.
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PMID:Molecular basis of glutamate toxicity in retinal ganglion cells. 942 25

1. Glutamate is the neurotransmitter released by bipolar cells at their synapses with amacrine cells. The amacrine cells express ionotropic (NMDA, AMPA and kainate) and metabotropic (mGluR1, mGluR2, mGluR4 and mGluR7) glutamate receptors and may take up glutamate from the synaptic cleft. 2. Activation of the ionotropic glutamate receptors increases the intracellular free calcium concentration ([Ca2+]i), owing to Ca2+ entry through the receptor-associated channels as well as through voltage-gated Ca2+ channels. The [Ca2+]i response to glutamate may be amplified by Ca2+-induced Ca2+ release from intracellular sources. 3. Activation of NMDA and non-NMDA glutamate receptors stimulates the release of GABA and acetylcholine from amacrine cells. GABA is released by a Ca2+-dependent mechanism and by reversal of the neurotransmitter transporter. 4. Excessive activation of glutamate receptors during ischemia leads to amacrine cell death. An increase in [Ca2+]i due to Ca2+ influx through NMDA and AMPA/kainate receptor channels is related to cell death in studies in vitro. In other studies, it was shown that nitric oxide may also take part in the process of cell damage during ischemia.
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PMID:Glutamate in life and death of retinal amacrine cells. 951 76

1. Glutamate (Glu) uptake in neurons and astrocytes is essential to prevent the persistence of excitotoxic levels of Glu in the synaptic cleft. 2. We investigated the effect of oxidative stress, which is also involved in ischemia-reperfusion, on the Glu transporter in isolated rat retinal cells. 3. Hydrogen peroxide (H2O2 3-300 microM) decreases the Na+-dependent Glu uptake. This effect is not related to a free radical production and is partly reversed by reducing agents, suggesting a transporter modulation by a redox-related event.
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PMID:Free radicals and glutamate uptake in the retina. 951 79

Neurons in the neonatal mammalian brain survive greater degrees of hypoxic stress than those in the mature brain. To investigate how developmental changes in glutamate receptor-mediated neurotoxicity contribute to this difference, we measured hypoxia-evoked glutamate release, glutamate receptor contribution to hypoxia-evoked intracellular calcium changes, and survival of hypoxia-/ischemia-sensitive CA1 neurons in rat hippocampus. Glutamate release was measured by a fluorescence assay, calcium changes in CA1 neurons with fura-2, and cell viability using Nissl and fluorescence staining with calcein-AM/ethidium homodimer, all in 300-micron thick hippocampal slices from 3-30 post-natal day (PND) rats. Glutamate released from PND 3-7 slices during hypoxia (PO2 = 5 mmHg) was only one third that of PND 18-22 slices. In PND 3-7 slices, survival of CA1 neurons after 5 min of hypoxia and 6 h of recovery was significantly greater than in PND 18-22 slices (viability indices 0.60 and 0.28, respectively, (p < 0.05). Five min of anoxia significantly altered Nissl staining pattern and morphology of CA1 neurons in PND 18-22 but not PND 3-7 slices. Hypoxia (PO2 = 5 mm Hg) caused three to five times greater increases in [Ca2+]i in PND 18-22 slices than in PND 3-7 slices (p < 0.001). During re-oxygenation, [Ca2+]i returned to baseline in PND 3-7 slices, but remained elevated in PND 18-22 slices. Glutamate receptor-mediated calcium changes in CA1 during hypoxia were 33% and 62% of the total calcium change in PND 3-7 and PND 18-22 CA1, respectively. We conclude that survival of CA1 neurons in PND 3-7 slices following hypoxic stress is associated with smaller increases and enhanced recovery of [Ca2+]i, less accumulation of glutamate, and less glutamate receptor-mediated calcium influx than in PND 18-22 slices.
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PMID:Hypoxia-tolerant neonatal CA1 neurons: relationship of survival to evoked glutamate release and glutamate receptor-mediated calcium changes in hippocampal slices. 955 54

Glutamate is a major neurotransmitter in the CNS. Its release activates NMDA and non-NMDA receptors on the postsynaptic membrane. NMDA receptor activation is shown to be important in physiological and pathological events. The modulatory sites on the NMDA receptor-channel ionophore complex are important in the regulation of the channel's cation conductance. Regulation of the channel by proton concentration may be important in the alkalinization that occurs during the normal release of glutamate or in the acidification that occurs during hypoxia/ischemia. In this study, the selective downregulation of the NMDA channel with slight extracellular pH changes and reversibility of this modulation have been shown in hippocampal slices. It has also been shown that hippocampal slices are more responsive to pH changes than other experimental preparations. The downregulation of the NMDA current may represent a native control mechanism. Direct and indirect modulation caused by extracellular pH changes on the NMDA receptor ionophore complex might be important in the overall response of the neuron under pathophysiological changes.
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PMID:The protective role of mild acidic pH shifts on synaptic NMDA current in hippocampal slices. 955 80

This review describes the techniques to evaluate retinal neurodegeneration induced by excitatory amino acids and transient ischemia. Glutamate-induced neurotoxicity was examined in cultured rat cortical cells. Cultures obtained from the retinas of fetal rats were incubated in Eagle's minimal essential medium supplemented with 10% fetal calf serum or 10% horse serum at 37 degrees C in a humidified 5% CO2 atmosphere for 10-14 days. The neurotoxicity induced by glutamate was quantified by trypan blue exclusion. The viability of cultures was markedly reduced by a 10-min exposure to glutamate followed by incubation with glutamate-free medium for 1 hr. N-methyl-D-aspartate (NMDA)-induced retinal damage was examined in adult rats. Transverse sections of the retinas through the optic disk were stained with hematoxylin and eosin. A single intravitreal injection of NMDA damaged the ganglion cell layer and the inner plexiform layer without affecting the other retinal layers 7 days after injection. Retinal ischemia was induced by elevating the intraocular pressure for 45 min through the needle which was placed in the anterior chamber. Ischemia-induced retinal damage was inhibited by MK-801. These results indicate that the techniques described in this review can be employed to develop new drugs possessing neuroprotective action against neurodegeneration that occurs during retinal ischemia.
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PMID:[Techniques for evaluating neuronal death of the retina in vitro and in vivo]. 955 48

Glutamate release after ischemia, hypoxia and seizure activity plays an important role in stimulating adenosine production and release. We characterized the ionotropic glutamate receptor subtype that regulates adenosine levels in vivo and investigated the role of nitric oxide and free radicals in mediating N-methyl-D-aspartate (NMDA)-induced increases in adenosine levels. Rats received unilateral intrastriatal injections and were sacrificed 15 min postinjection by high-energy focused microwave irradiation (10 kW, 1.25 s). Adenosine levels were measured by high-performance liquid chromatography in ipsilateral and contralateral striata. NMDA and kainic acid dose-dependently increased levels of adenosine whereas (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazol proprionic acid had no effect. The NMDA- and kainic acid-induced increases were blocked by dizocilpine, and the kainic acid response was decreased by 6-cyano-7-nitroquinoxaline-2,3-dione. The effects of NMDA and kainic acid on levels of adenosine were not additive. Intrastriatal L-arginine decreased, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, increased basal adenosine levels. Coadministration of NMDA with L-arginine or NG-nitro-L-arginine methyl ester did not significantly affect NMDA-induced increases in levels of adenosine. N-Tert-butyl-phenylnitrone, a free radical scavenger, reversed L-arginine-induced decreases and NMDA-induced increases in levels of adenosine. Together, these results indicate that NMDA-type ionotropic receptors play an important role in regulating in vivo levels of adenosine in rat striatum and that free radicals, but not nitric oxide, apparently are involved in NMDA-induced increases in levels of adenosine. Conversely, nitric oxide, but not free radicals, apparently exert tonic control over basal levels of endogenous adenosine.
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PMID:Levels of endogenous adenosine in rat striatum. I. Regulation by ionotropic glutamate receptors, nitric oxide and free radicals. 958 May 98


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