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

This study demonstrates ischemic cellular swelling in vivo detected as changes in the concentration of 14C-sucrose pre-perfused into the extracellular space (ECS) as an ECS marker. Microdialysis was utilized as a means of perfusion and measurement of the extracellular concentration of 14C-sucrose ([14C-sucrose]e). Concomitant with an abrupt increase in [K+]e at 1-3 min following the ischemia induction, [14C-sucrose]e was also rapidly elevated. Since sucrose is not taken up by either cells or capillaries, the absolute amount of 14C-sucrose in the ECS must be unchanged. The increase therefore appears to represent a relative decrease in water volume in the ECS resulting from a movement of water into the cells, i.e. cellular swelling. Ca(2+)-free perfusate containing Co2+, which has been shown to block excitatory amino acid release during cerebral ischemia, significantly delayed the increase in [14C-sucrose]e and [K+]e. Kynurenic acid, a broad-spectrum antagonist of excitatory amino acids, administered in situ through the dialysis probe also significantly delayed the increase in [14C-sucrose]e and [K+]e. These findings indicate that the early cellular swelling occurring during cerebral ischemia is a result of massive ionic fluxes mediated by excitatory amino acids which are released by a Ca(2+)-dependent exocytotic process from the nerve terminals.
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PMID:Early cellular swelling during cerebral ischemia in vivo is mediated by excitatory amino acids released from nerve terminals. 132 56

We assessed the effect of a broad spectrum glutamatergic receptor antagonist, kynurenic acid (500 mg/kg) on ischemia-induced hippocampal glutamate release and neuronal damage. Kynurenic acid significantly decreased glutamate release during ischemia but had no effect on the hippocampal lesion. Some protection was observed in the cortex and in the striatum. These data suggested that the extracellular accumulation of glutamate during forebrain ischemia does not play a major role in the hippocampus.
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PMID:Inhibition of glutamate release in rat hippocampus by kynurenic acid does not protect CA1 cells from forebrain ischemia. 136 Mar 14

Kynurenic acid is the only known endogenous excitatory amino acid receptor antagonist in the central nervous system. In the present study, we examined whether increasing brain concentrations of kynurenic acid by loading with its precursor L-kynurenine, or blocking its excretion with probenecid, could exert neuroprotective effects. Neuroprotective effects were examined in a neonatal model of hypoxia-ischemia, and following intrastriatal injection of N-methyl-D-aspartate (NMDA). Seven-day-old rats underwent unilateral ligation of the carotid artery, followed by exposure to 8% oxygen for 1.5 h. L-kynurenine administered 1 h before the hypoxia-ischemia showed a dose-dependent significant neuroprotective effect, with complete protection at a dose of 300 mg kg-1. The induction of c-fos immunoreactivity in cerebral cortex was also blocked by this dose of L-kynurenine. Probenecid alone had moderate neuroprotective effects, while a combination of a low dose of probenecid with doses of 50-200 mg kg-1 of L-kynurenine showed significant dose-dependent neuroprotection. Kynurenine dose-dependently protected against NMDA neurotoxicity in 7-day-old rats. Neurochemical analysis confirmed that L-kynurenine with or without probenecid markedly increased concentrations of kynurenic acid in cerebral cortex of 7-day-old rats. These results show for the first time that pharmacologic manipulation of endogenous concentrations of kynurenic acid can exert neuroprotective effects.
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PMID:Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats. 156 35

The metabolic effects of kynurenate, an endogenous excitatory amino acid antagonist, were studied by in vivo 31P-NMR spectroscopy before, during and after reversible forebrain ischemia in the rat. Kynurenate had no effect on cerebral metabolism before ischemia. During a 30-min ischemia, kynurenate protected against the decrease in phosphocreatine (up to -55 +/- 3% vs -73 +/- 3% in the reference group) and the increase in inorganic phosphate (up to +479 +/- 39% vs +805 +/- 66%), whereas there was no statistical difference in the decrease in intracellular pH (up to 6.37 +/- 0.05 vs 6.30 +/- 0.03) and ATP (up to -60 +/- 3% vs -60 +/- 7%). The recovery of PCr, Pi, and pHi to control levels during recirculation was faster in the treated group than in the reference group, whereas the time course of ATP recovery was similar in both groups. We conclude that kynurenate protects against neuronal loss, as previously reported, by mechanisms other than metabolic protection.
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PMID:Metabolic effects of kynurenate during reversible forebrain ischemia studied by in vivo 31P-nuclear magnetic resonance spectroscopy. 188 1

The neuroprotective effect of kynurenic acid, an unspecific antagonist of excitatory amino acid receptors, was evaluated in a model of hypoxic-ischemia in neonatal rats. One-week-old rats were subjected to ligation of the left carotid artery and exposure to 7.7% O2/92.3% N2 for 2 h. Kynurenic acid (300 mg/kg) was administered i.p. immediately after the period of hypoxic-ischemia in one group (n = 32) and compared with saline-treated (n = 27). After 2 weeks the rats were sacrificed and the brain damage evaluated by comparing the weight of the lesioned and unlesioned hemispheres. In rats receiving kynurenic acid the reduction in weight of the lesioned hemisphere was 25.4 +/- 3.3% as compared to 37.8 +/- 3.6% in saline-treated controls (P less than 0.001). The results suggest that excitatory amino acids are involved in the development of postischemic damage in the immature brain.
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PMID:The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection. 341 43

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global ischemia/reperfusion and hypoglycemia. The current investigations extend these observations to a model of focal ischemia. Kynurenic acid, a broad-spectrum antagonist at excitatory amino acid receptors, was used as treatment (300 mg/kg; 3 doses at 4-hour intervals) before and after focal cerebral ischemia in rats (n = 54). Preischemia but not 1 hour postischemia treatment with kynurenate attenuated infarction size (p less than 0.001) and improved neurological outcome (p less than 0.001) studied at 24 hours after injury. These data support the role of excitatory neurotransmission in acute neuronal injury and support pharmacological inhibition of cell excitation as a potential therapy for stroke.
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PMID:Kynurenate inhibition of cell excitation decreases stroke size and deficits. 343 82

We examined the effect of kynurenic acid, a broad spectrum antagonist of excitatory amino acid receptors, on striatal extracellular glutamate and aspartate accumulation induced by a 30 min forebrain ischaemia in rats. Kynurenic acid, given systemically (500 mg kg-1, i.p.) or administered in situ through the dialysis probe (10 mM), markedly depressed the ischaemia-induced increase in glutamate and aspartate concentrations. These results indicate that, during forebrain ischaemia, local glutamate receptors play a major role in glutamate and aspartate accumulation in the striatum. Ischaemia-induced increase in extracellular concentrations of these excitatory amino acids may be due in part to a positive glutamatergic feedback loop via activation of NMDA and/or non-NMDA receptors.
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PMID:Effect of kynurenic acid on the ischaemia-induced accumulation of glutamate in rat striatum. 791 86

The effect of selective antagonists (7-Cl-kynurenic acid, 3-amino-1-hydroxypyrrolid-2-one (HA 966) and GV 150526A) at strychnine-insensitive glycine sites was studied by measuring how much glycine potentiated the [3H]dopamine and [3H]noradrenaline release induced by 100 microM N-methyl-D-aspartate (NMDA) from superfused striatal and hippocampal synaptosomes, respectively, in a Mg2+-free buffer. Glycine, which per se had no effect on [3H]catecholamine release, concentration-dependently potentiated the effect of NMDA, with similar potency in the two brain regions (EC50 0.25 and 0.27 microM for [3H]dopamine and [3H]noradrenaline release, respectively). 7-Cl-Kynurenic acid reduced the effect of NMDA alone and antagonized the effect of 1 microM glycine, with Ki values of 1.1 and 0.6 microM for [3H]dopamine and [3H]noradrenaline release, respectively. HA 966 did not inhibit the effect of NMDA alone, but reduced the effect of glycine with Ki = 11.5 and 66 microM for [3H]dopamine and [3H]noradrenaline release. GV 150526A inhibited the effect of NMDA alone and potently antagonized the effect of glycine, with Ki = 12.4 and 17.3 nM for [3H]dopamine and [3H]noradrenaline release. Our results are consistent with the possibility that HA 966 is a partial agonist, while 7-Cl-kynurenic acid and GV 150526A are competitive antagonists at the strychnine-insensitive glycine sites. In addition HA 966 shows regional differences in its interaction with the strychnine-insensitive glycine receptor, being about six times more potent on striatal than on hippocampal synaptosomes, suggesting a possible heterogeneity of glycine sites recognized by HA 966 or different intrinsic activity in the two brain regions. The nanomolar potency of GV 150526A in reducing NMDA receptor function by competitively acting at the strychnine-insensitive glycine sites suggests that GV 150526A could be effective in vivo to reduce NMDA receptor over-stimulation, like in brain ischemia.
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PMID:GV 150526A, 7-Cl-kynurenic acid and HA 966 antagonize the glycine enhancement of N-methyl-D-aspartate-induced [3H]noradrenaline and [3H]dopamine release. 938 43

Slices of somatosensory cortex taken from immature rats on postnatal day (P)7-14 were labeled with fura-2. Intracellular Ca2+ concentration ([Ca2+]i) was monitored in identified pyramidal cells as the ratio of fluorescence intensities (RF340/F380) during oxygen-glucose deprivation. The RF340/F380 ([Ca2+]i) of individual pyramidal cells was monitored in each of the cortical layers II-VI simultaneously. Neurons in all neocortical layers exhibited significant increases in [Ca2+]i that varied with the duration of oxygen-glucose deprivation. Individual neurons responded to oxygen-glucose deprivation with abrupt increases in [Ca2+]i after various latencies. The ceiling level of the [Ca2+]i increase differed from cell to cell. Neurons in layer II/III showed significantly greater increases in [Ca2+]i than those in layers IV, V, or VI. Kynurenic acid, a nonselective glutamate receptor antagonist, and bicuculline, a selective gamma-aminobutyric acid (GABA)A receptor antagonist, suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all neocortical layers examined. After kynurenic acid, but not after bicuculline, there was no longer a differential [Ca2+]i increases in layer II/III. Both 2-amino-5-phosphonopentanoic acid (AP5), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, strongly suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all layers. The laminar difference in terms of the [Ca2+]i increases was abolished by AP5, but not by CNQX. These results indicate that layer II/III cells are the most prone to oxygen-glucose deprivation-induced intracellular Ca2+ accumulation, and that this is primarily mediated by NMDA receptors. Thus, layer II/III neurons would be more likely to suffer cellular Ca2+ overload and excitotoxicity during ischemia than layer IV-VI cells. Such a differential laminar vulnerability might play an important role in determining the pathological characteristics of the immature cortex and its sequelae later in life.
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PMID:NMDA receptor-mediated differential laminar susceptibility to the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in rat neocortical slices. 942 11

1. Kynurenic acid (KYNA) is a kynurenine metabolite and a broad spectrum excitatory amino acid antagonist that has been shown to be neuroprotective in models of cerebral ischemia, when administered exogenously. However, the actual concentration required in the CNS to evoke significant neuroprotection has never been assessed. 2. The purpose of this study was to address this question in the gerbil model of forebrain ischemia. KYNA (400-1600 mg/kg) or vehicle were administered i.p. 15 min before 5 min bilateral carotid occlusion. 3. Seven days after reperfusion, ischemia-induced hippocampal nerve cell loss (95% in vehicle-treated) was significantly lower in KYNA-treated gerbils (65% and 52% at 1000 and 1200 mg/Kg, respectively, P < 0.01). Treatment with 1000 mg/kg produced brain KYNA concentrations that were dramatically elevated (135.9 and 42.3 microM in CSF and whole brain, vs 0.032 and 0.16 microM in controls, at 15 min after ischemia), as measured in a separate group of transcardially-perfused gerbils. Cerebral KYNA concentrations tended to return to basal values 2 hours after reperfusion. 4. These results indicate that KYNA has a marked neuroprotective effect in a model of forebrain ischemia. This activity is associated with KYNA concentrations in the brain and CSF that are compatible with the in vitro affinity of the compound for ionotropic glutamate receptors.
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PMID:Brain concentrations of kynurenic acid after a systemic neuroprotective dose in the gerbil model of global ischemia. 1039 Jul 31


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