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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive activation of glutamate receptors is neurotoxic, contributing to brain injury caused by cerebral ischemia. The pharmacology of glutamate neurotoxicity is difficult to study in animals because it is efficiently cleared from the extracellular space by a family of glutamate transporters. We have investigated the receptor specificity of endogenous glutamate's toxic effects in organotypic cultures of the hippocampus by acute blockade of these transporters. The organotypic cultures used in these transporters. The organotypic cultures used in these experiments preserve the intrinsic connections and regional differentiation of the hippocampus in long term culture and may more closely reproduce the pharmacology of the mature brain region. Membrane injury was measured with digital fluorescence imaging of the vital dye, propidium iodide, 24 h after a 30-min exposure to glutamate receptor agonists or to antagonists of glutamate transport. Confirming our previous results, bath-applied, exogenous glutamate caused dose-dependent neuronal injury. Glutamate was less potent than the selective agonists NMDA, AMPA, and quisqualate. Blockade of glutamate transport with the selective antagonists threo-hydroxy-aspartate and pyrrolidine-dicarboxylic acid also caused dose-dependent neuronal injury. Endogenous or exogenous glutamate toxicity was caused by a coactivation of both NMDA and AMPA/kainate receptors; blockade of either was sufficient to substantially prevent neuronal injury. Protective effects of combined application of antagonists were generally less than additive. We conclude that AMPA/kainate receptors play a more prominent role in glutamate neurotoxicity in organotypic cultures than in dissociated cortical or hippocampal cultures, acting together with NMDA receptors to cause neuronal injury.
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PMID:Neurotoxicity of acute glutamate transport blockade depends on coactivation of both NMDA and AMPA/Kainate receptors in organotypic hippocampal cultures. 754 69

1. Cortical spreading depression (SD) is a propagating transient suppression of electrical activity associated with depolarization, which may contribute to the pathophysiology of important neurological disorders, including cerebral ischemia and migraine. The purpose of this study is to ascertain whether SD propagation depends on local accumulation of extracellular K+ or glutamate. 2. Propagating SD recorded through microdialysis probes perfused with artificial cerebrospinal fluid (ACSF) was much smaller than that recorded with conventional glass microelectrodes, presumably because some SD-induced transient changes in the extracellular fluid composition were buffered by ACSF. We have exploited this effect to determine whether perfusion with a medium containing increasing amounts of K+ and/or glutamate favors SD propagation. 3. Increasing the concentration of K+ (15-60 mmol/l) in the perfusion medium dose-dependently restored SD propagation, whereas application of 100-250 mumol/l glutamate through the microdialysis probe had no effect. Superimposing 200 mumol/l glutamate onto 15 and 30 mmol/l K+ did not further improve the restoration of SD propagation by K+. 4. Because potent uptake mechanisms may efficiently clear exogenous glutamate from the extracellular space, the effect of local inhibition of high-affinity glutamate uptake was also studied. Perfusion of the recording microdialysis probe with 1 mmol/l L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), either alone or together with 200 mumol/l glutamate, had no effect. In addition, L-trans-PDC did not potentiate the positive effect of 30 mmol/l K+ on SD propagation. 5. These results strongly suggest that high extracellular K+, and not extracellular glutamate, is the driving force sustaining SD propagation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High extracellular potassium, and not extracellular glutamate, is required for the propagation of spreading depression. 762 2

It has been proposed that deficient glutamate uptake, by increasing the extracellular concentration of this excitatory neurotransmitter, may contribute to the pathophysiology of cerebral ischaemia. This study aimed to examine whether pharmacological inhibition of glutamate uptake altered the kinetics of ischaemia-induced glutamate efflux, and precipitated anoxic depolarisation. Microdialysis was used for application of the glutamate-uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), recording of the EEG and extracellular direct current (DC) potential with an electrode within the probe, and continuous monitoring of changes in extracellular glutamate. L-trans-PDC was applied locally from 8 min prior to cardiac arrest to the end of the recording period. L-trans-PDC (2.5 mM) barely altered the time course of postmortem glutamate efflux in the cortex. Only the maximum rate of efflux during the first exocytotic phase, and the concentration reached at the end of this phase, appeared slightly increased. L-trans-PDC (5 mM) reduced significantly the delay between EEG silence and anoxic depolarization in the cerebral cortex (59.2 +/- 9.2 s vs. 79.7 +/- 11.5 s; n = 6), but not in the striatum and hippocampus. These effects contrast with the marked increase in dialysate glutamate that L-trans-PDC produces in all these three brain regions. Together, these data do not support the hypothesis that inhibition of glutamate uptake plays a critical role, early in cerebral ischaemia. However, a contribution of reversed glutamate uptake to the secondary Ca2+-independent phase of ischaemia-induced glutamate efflux cannot be ruled out.
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PMID:Effects of pharmacological inhibition of glutamate-uptake on ischaemia-induced glutamate efflux and anoxic depolarization latency. 955 Feb 92

Effects of chronic (14-day) pretreatment of orally administered pyrrolidine dithiocarbamate (PDTC) (100 or 200 mg/kg/day) on alcohol-induced venular cerebrovasospasm, microvessel rupture, leukocyte-endothelial chemoattraction, and microhemorrhaging was studied by direct, quantitative in vivo high-resolution TV microscopy of the intact rat brain. Sham animals chronically treated with placebo exhibited concentration-dependent venular cerebrovasospasm, endothelial-leukocyte rolling and attraction, microvessel rupture. and focal hemorrhages, irrespective of route (i.e., perivascular, systemic) of ethanol administration. PDTC pretreatment either prevented or ameliorated greatly the cerebrovasospasm, leukocyte-endothelial chemoattraction, and brain vascular damage induced by ethanol. These new data suggest that alcohol induces cerebral vascular and brain damage by reperfusion injury events, which trigger induction of proinflammatory factors, and transcription factor NF-kappaB and lipid peroxidation of vascular smooth muscle and endothelial cell membranes; these proinflammatory, pro-oxidant, and redox events could play a crucial role in the pathogenesis of alcohol-induced cerebral ischemia and stroke.
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PMID:Pyrrolidine dithiocarbamate attenuates alcohol-induced leukocyte-endothelial cell interaction and cerebral vascular damage in rats: possible role of activation of transcription factor NF-kappaB in alcohol brain pathology. 965 Jun 33

Nitric oxide (NO) overproduction has been postulated to contribute significantly to ischaemia-reperfusion neurotoxicity. Inducible or type II NO synthase (iNOS) synthesizes NO in large quantities for long periods of time. Therefore we investigated the expression and localization of iNOS after oxygen and glucose deprivation in rat forebrain slices. In this experimental model, calcium-independent NOS activity reached a maximum 180 min after the end of a 20 min oxygen-glucose deprivation period. During the same period of time, the calcium-independent activity was absent in control forebrain slices. To test whether this calcium-independent NOS activity was due to the expression of iNOS, the effects of the addition of dexamethasone, cycloheximide and pyrrolidine dithiocarbamate were determined. All of them inhibited the induction of the calcium-independent NOS activity measured in the rat forebrain slices after oxygen and glucose deprivation. Furthermore, oxygen and glucose deprivation caused the expression of the gene encoding iNOS in rat forebrain slices, as assessed by the detection of iNOS message and protein in these samples. A sixfold increase in the iNOS mRNA levels was observed at 180 min and the time-course of the expression of iNOS mRNA was in agreement with the temporal profile of iNOS enzymatic activity. Immunohistochemistry analysis revealed that iNOS was highly expressed in neurones, astrocytes and microglial cells. These results demonstrate for the first time that iNOS is expressed in neurones after oxygen and glucose deprivation, and that this expression occurs in short periods of time. These findings suggest that NO can play an important pathogenic role in the tissue damage that occurs after cerebral ischaemia.
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PMID:Neuronal expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. 974 7

Nitric oxide synthesis by inducible nitric oxide synthase (iNOS) has been postulated to contribute to ischemia-reperfusion neurotoxicity. The expression of this enzyme has been demonstrated in cells present in the postischemic brain. The mechanisms of iNOS expression after cerebral ischemia are a subject of current research. We therefore decided to investigate whether glutamate, which is released in ischemia and is implicated in neurotoxicity, might be involved in the mechanisms by which oxygen and glucose deprivation (OGD) leads to the expression of iNOS in rat forebrain slices. In this model, we have shown previously that 20 min of OGD causes the expression of iNOS. We have now found that the NMDA receptor antagonist MK-801 blocks the expression of iNOS, suggesting that the activation of the NMDA subtype of glutamate receptor is implicated in the mechanisms that lead to the expression of this isoform. Moreover, we have found that glutamate alone could trigger the induction process, as shown by the appearance of a Ca(2+)-independent NOS activity and by the detection of iNOS mRNA and protein in slices exposed to glutamate. Glutamate-dependent iNOS expression was concentration-dependent and was blocked by EGTA and by the inhibitors of nuclear factor kappaB (NF-kappaB) activation pyrrolidine dithiocarbamate and MG132. In addition, glutamate induced NF-kappaB translocation to the nucleus, an effect that was inhibited by MG132. Taken together, our data suggest that activation of NMDA receptors by glutamate released in ischemia is involved in the expression of iNOS in rat forebrain slices via a Ca(2+)-dependent activation of the transcription factor NF-kappaB. To our knowledge, this is the first report showing an implication of excitatory amino acids in the expression of iNOS caused by ischemia.
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PMID:Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. 1080 Sep 47

The extracellular glutamate concentration ([glu](o)) rises during cerebral ischemia, reaching levels capable of inducing delayed neuronal death. The mechanisms underlying this glutamate accumulation remain controversial. We used N-methyl-D-aspartate receptors on CA3 pyramidal neurons as a real-time, on-site, glutamate sensor to identify the source of glutamate release in an in vitro model of ischemia. Using glutamate and L-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC) as substrates and DL-threo-beta-benzyloxyaspartate (TBOA) as an inhibitor of glutamate transporters, we demonstrate that energy deprivation decreases net glutamate uptake within 2-3 min and later promotes reverse glutamate transport. This process accounts for up to 50% of the glutamate accumulation during energy deprivation. Enhanced action potential-independent vesicular release also contributes to the increase in [glu](o), by approximately 50%, but only once glutamate uptake is inhibited. These results indicate that a significant rise in [glu](o) already occurs during the first minutes of energy deprivation and is the consequence of reduced uptake and increased vesicular and nonvesicular release of glutamate.
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PMID:Acute decrease in net glutamate uptake during energy deprivation. 1080 15

The effect of diethylmaleate administration on ascorbic acid release following cerebral ischemia was investigated in anesthetized rat brain cortex. Cerebral ischemia, induced by ligating bilateral common carotid arteries and unilateral middle cerebral artery, significantly increased the extracellular ascorbic acid levels. Diethylmaleate (4 mmoles/kg, i.p.), which has been shown in earlier studies to decrease the ischemia-induced glutamate release, significantly reduced the ischemia-induced ascorbic acid release. The ischemia-induced ascorbic acid release was unaffected by perfusing NMDA receptor antagonist MK 801 (75 microM). Additionally, elevated extracellular glutamate levels, achieved by either externally applied glutamate solutions or by perfusing L-trans-pyrrolidine-2,4-dicarboxylate (PDC) (31.4 mM and 15.7 mM) to inhibit the glutamate uptake transporter, also significantly increased the extracellular ascorbic acid levels. These results suggested that ascorbic acid release in cerebral ischemia might be related to the elevated extracellular glutamate levels, which occurs following cerebral ischemia.
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PMID:Diethylmaleate decreased ascorbic acid release induced by cerebral ischemia in cerebral cortex of the anesthetized rat. 1099 93

Endogenous reactive oxygen species (ROS) can act as modulators of neuronal activity, including synaptic transmission. Inherent in this process, however, is the potential for oxidative damage if the balance between ROS production and regulation becomes disrupted. Here we report that inhibition of synaptic transmission in rat hippocampal slices by H2O2 can be followed by electrical hyperexcitability when transmission returns during H2O2 washout. As in previous studies, H2O2 exposure (15 min) reversibly depressed the extracellular population spike (PS) evoked by Schaffer collateral stimulation. Recovery of PS amplitude, however, was typically accompanied by mild epileptiform activity. Inclusion of ascorbate (400 microM) during H2O2 washout prevented this pathophysiology. No protection was seen with isoascorbate, which is a poor substrate for the stereoselective ascorbate transporter and thus remains primarily extracellular. Epileptiform activity was also prevented by the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5) during H2O2 washout. Once hyperexcitability was induced, however, AP5 did not reverse it. When present during H2O2 exposure, AP5 did not alter PS depression by H2O2 but did inhibit the recovery of PS amplitude seen during pulse-train stimulation (10 Hz, 5 s) in H2O2. Inhibition of glutamate uptake by l-trans-2,4-pyrrolidine dicarboxylate (PDC; 50 microM) during H2O2 washout markedly enhanced epileptiform activity; coapplication of ascorbate with PDC prevented this. These data indicate that H2O2 exposure can cause activation of normally silent NMDA receptors, possibly via inhibition of redox-sensitive glutamate uptake. When synaptic transmission returns during H2O2 washout, enhanced NMDA receptor activity leads to ROS generation and consequent oxidative damage. These data reveal a pathological cycle that could contribute to progressive degeneration in neurological disorders that involve oxidative stress, including cerebral ischemia.
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PMID:NMDA receptor activation mediates hydrogen peroxide-induced pathophysiology in rat hippocampal slices. 1203 93

An increased concentration of extracellular glutamate is associated with neuronal damage induced by cerebral ischemia. We have demonstrated previously that exposure of cultured cerebellar granule neurons to L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a glutamate uptake inhibitor, increases extracellular glutamate levels but does not induce neuronal damage. Coincubation of PDC, however, with a subthreshold concentration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), results in severe damage to these neurons. We have investigated the time course of changes in mitochondrial reducing capacity and ATP levels in cerebellar granule cells after simultaneous exposure to 3-NP and PDC, and its relation to cell viability and nuclear condensation. Although individually, 3-NP and PDC treatments are not harmful to neurons, the simultaneous exposure to both compounds results in a progressive decline in mitochondrial reducing capacity during the first 4 hr, and a rapid decrease in ATP levels. At 4 hr, cells lose plasma membrane integrity and show condensed nuclei. In the presence of the energy substrates pyruvate and acetoacetate, the N-methyl-D-apartate (NMDA) receptor antagonist, MK-801, and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN), the decline in mitochondrial activity and ATP levels is prevented, the number of condensed nuclei is reduced, and plasma membrane integrity is preserved. In contrast, the broad-spectrum caspase inhibitor Z-Asp-DCB (Z-Asp-CH2-DCB) prevents nuclear condensation but has no effect on mitochondrial reducing capacity or cell survival. Our results show that glutamate uptake impairment rapidly induces neuronal death during inhibition of succinate dehydrogenase by a mechanism involving mitochondrial dysfunction that, if not prevented, leads to cell death.
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PMID:Glutamate uptake inhibitor L-trans-pyrrolidine 2,4-dicarboxylate becomes neurotoxic in the presence of subthreshold concentrations of mitochondrial toxin 3-nitropropionate: involvement of mitochondrial reducing activity and ATP production. 1464 2


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