Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During cerebral ischemia, the expression of interleukin-6 (IL-6), which has neuroprotective properties, increases. To understand the underlying mechanism, the regulation of IL-6 expression by neurotransmitters that accumulate during cerebral ischemia was investigated. Adenosine stimulated IL-6 secretion in primary astrocytes four- to 10-fold. The effect was concentration dependent, the EC50 being approximately 8 microM. Although the nonselective analogue 2-chloroadenosine (2CA) increased IL-6 secretion to a similar extent, the A1-selective agonist N6-cyclopentyladenosine or the A2a agonist CGS-21680 had only a marginal effect on IL-6 secretion. IL-6 secretion stimulated by 2CA (10 microM) was inhibited by the nonselective adenosine antagonist 8-(p-sulfophenyl)theophylline, whereas the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine or the A2a-selective antagonist 8-(3-chlorostyryl)caffeine had no effect, to a concentration of 0.1 microM. Transcription of the IL-6 gene was investigated by transfecting primary astrocytes with a reporter fusion gene containing the human IL-6 promoter (-179/+12). 2CA stimulated IL-6 gene transcription 2.5-fold. Mutations of the binding site for NF-kappaB or NF-IL6 abrogated the response to 2CA. Thus, an increase of extracellular adenosine during focal cerebral ischemia may stimulate IL-6 expression via A2b receptors. The induction of IL-6 expression appears to involve a transcriptional effect that depends on NF-kappaB and NF-IL6.
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PMID:Stimulation of interleukin-6 secretion and gene transcription in primary astrocytes by adenosine. 928 37

Tissue adenine nucleotides are depleted during cerebral ischemia, impeding recovery after reperfusion. Although prior studies have attempted to prevent the initial loss of adenylates, the present study tests the hypothesis that stimulating synthesis of adenine nucleotides, through either adenosine kinase or adenine phosphoribosyltransferase, would result in significant cerebroprotection. To study the effects on neurons and glia directly while avoiding the influence of the cerebral vasculature, hippocampal brain slices were used for the model of transient ischemia with reperfusion. The standard brain slice insult of brief exposure to anoxia with aglycemia was modified based on studies which showed that a 30-minute exposure to air with 1 mmol/L glucose produced a stable, moderate reduction in ATP during the insult and that, 2 hours after return to normal conditions, there was moderate depletion of tissue adenine nucleotides and histologic injury. Treatments with 1 mmol/L adenosine, AMP, or adenine were equivalent in partially restoring adenine nucleotides. Despite this, only adenosine afforded histologic protection, suggesting a protective role for adenosine receptors. There also was evidence for metabolic cycling among adenine nucleotides, nucleosides, and purines. Adenosine may exert direct cerebroprotective effects on neural tissue as well as indirect effects through the cerebral vasculature.
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PMID:Restoring adenine nucleotides in a brain slice model of cerebral reperfusion. 962 92

Adenosine has been reported to have beneficial effects against ischemic brain damage, although the mechanisms are not fully clarified. To examine the role of adenosine on the ischemia-evoked release of neurotransmitters, we applied a highly selective agonist for adenosine A1 receptor, 2-chloro-N6-cyclopentyladenosine (CCPA), into the ischemic brain using in vivo brain dialysis, which directly delivered the agonist to the local brain area. Concentrations of extracellular amino acids (glutamate, aspartate, gamma-aminobutyric acid (GABA) and taurine) and regional blood flow in the striatum of spontaneously hypertensive rats (SHRs) were monitored during cerebral ischemia elicited by bilateral carotid artery occlusion for 40 min and recirculation. Striatal blood flow and basal levels of amino acids were not affected by direct perfusion of CCPA (10 microM or 100 microM). During ischemia, concentrations of glutamate, aspartate, GABA and taurine increased up to 37-, 30-, 96- and 31-fold, respectively, when vehicle alone was administered. Administration of CCPA did not affect the changes in regional blood flow during ischemia and reperfusion. Perfusion of CCPA (100 microM), however, significantly attenuated the ischemia-evoked release of aspartate (by 70%) and glutamate (by 73%). The ischemia-induced increase of GABA tended to be decreased by CCPA, although it was not statistically significant. In contrast, both low and high concentrations of CCPA had little effect on the release of taurine during ischemia. These results suggest that stimulation of adenosine A1 receptors selectively attenuated the ischemia-evoked release of excitatory amino acids, but not of inhibitory amino acids without affecting blood flow. This modulation of the release of amino acids by adenosine A1 receptor agonists may play a protective role against ischemic neuronal damage.
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PMID:Modulation of ischemia-evoked release of excitatory and inhibitory amino acids by adenosine A1 receptor agonist. 979 30

Brain ischemia stimulates release from astrocytes of adenine-based purines, particularly adenosine, which is neuroprotective. Guanosine, which has trophic properties that may aid recovery following neurological damage, is present in high local concentrations for several days after focal cerebral ischemia. We investigated whether guanine-based purines, like their adenine-based counterparts, were released from astrocytes and whether their release increased following hypoxia/hypoglycemia. HPLC analysis of culture medium of rat astrocytes showed spontaneous release of endogenous guanine-based purines at a higher rate than their adenine-based counterparts. The concentration of guanosine (approximately 120 nM) and adenosine (approximately 43 nM) in the culture medium remained constant, whereas concentrations of adenine and guanine nucleotides, particularly GMP, and their metabolites increased with time. Exposure of the cultures to hypoxia/hypoglycemia for 30 min increased the extracellular concentration of adenine-based purines by 2.5-fold and of guanine-based purines by 3.5-fold. Following hypoxia/hypoglycemia extracellular adenine nucleotide levels increased further. Adenosine concentration increased, but not proportionally to nucleotide levels. Accumulation of adenosine metabolites indicated it was rapidly metabolized. Conversely, the concentrations of extracellular guanine-based nucleotides remained elevated and the concentration of guanosine continued to increase. These data indicate that astrocytes are a major source of guanine-based purines, the release of which is markedly increased following hypoxia/hypoglycemia, permitting them to exert neurotrophic effects.
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PMID:Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemia. 988 1

Adenosine is a "retaliatory metabolite" which accumulates during experimental brain ischemia and has vasodilatory and putative neuroprotective effects. The aim of this study was to assess whether human cerebral ischemia and necrosis-evaluated in the clinical models of transient ischemic attack (TIA) and stroke, respectively-acutely raise plasma adenosine levels. We studied 20 patients: 10 with TIA and 10 with stroke. In all, blood was serially sampled for assessment of plasma adenosine by an high-performance liquid chromatography method. Sampling occurred on peripheral blood during TIA and stroke upon admission, and serially thereafter every day up to 7 days and every other day up to 20 days. We found that in TIA and stroke patients, peripheral adenosine levels were increased to a similar extent upon admission (TIA = 264 +/- 53 vs. stroke = 257 +/- 60 nM, p = ns), peaked on the day 2 for TIA (300 +/- 60) and on day 3 for stroke (289 +/- 43) patients, and steadily decreased towards the normal range, reached by all TIA patients by day 5 and by stroke patients by day 15. Stroke and TIA are associated with a rapid increase in circulating plasma adenosine concentration in man, detectable in peripheral vein. The adenosine surge likely mirrors an increased production from the ischemic brain, and it lasts days (for TIA) and weeks (for stroke) after the acute event.
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PMID:Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke. 1070 83

Adenosine levels increase in brain during cerebral ischemia, and adenosine has receptor-mediated neuroprotective effects. This study was performed to test the hypothesis that nitrobenzylthioinosine (NBMPR), a selective and potent inhibitor of one adenosine transporter subtype termed ENT1, or es, can protect against ischemic neuronal injury by enhancing adenosine levels and potentiating adenosine receptor-mediated effects, including attenuation of the cellular production and release of tumor necrosis factor-alpha (TNF-alpha). In rats, the phosphorylated prodrug form of NBMPR, NBMPR-phosphate, or saline was administered by intracerebroventricular injection 30 min before forebrain ischemia. Seven days following the ischemic episode, rats were killed, and neuronal damage in the CA1 region of the hippocampus was assessed. The number of pyramidal neurons was significantly (p < 0.001) greater in the NBMPR-P treatment group. A trend toward protection was still evident at 28 days postreperfusion. Adenosine increased significantly during ischemia to levels eight- to 85-fold above basal. NBMPR-P treatment did not cause statistically significant increases in ischemic adenosine levels; however, this treatment tended to increase adenosine levels in all brain regions at 7 min postreperfusion. Ischemia-induced expression of TNF-alpha was not altered by NBMPR-P treatment, and the nonselective adenosine receptor antagonist 8-(p-sulfophenyl) theophylline did not abolish the neuroprotective effects of NBMPR-P treatment. These data indicate that NBMPR can protect CA1 pyramidal neurons from ischemic death without statistically significant effects on adenosine levels or adenosine receptor-mediated inhibition of the proinflammatory cytokine TNF-alpha.
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PMID:Effects of nitrobenzylthioinosine on neuronal injury, adenosine levels, and adenosine receptor activity in rat forebrain ischemia. 1089 57

Adenosine plays an important role in cerebral ischemia by acting on its own receptors, in particular the A(2A)receptor. Its activation leads to excitatory amino acid release thus contributing to the ischemic damage. Blockade by specific antagonists may protect against cytotoxic injury. Our study was aimed to investigate the effect of the blockade of A(2A)receptors, by Sch 58261, on the expression of the early gene c-fos, in a model of permanent middle cerebral artery occlusion (pMCAo), in rats. In the pMCAo model, ischemia was induced in the right hemisphere whereas the contralateral one was considered the control. In our study, we have compared pMCAo rats, pMCAo rats treated with Sch 58261 and sham operated ones.C-fos was markedly expressed in the ischemic hemispheres, whereas lower levels were detected in the contralateral ones of the ischemic animals. The lowest bands were observed in sham operated rats. After treatment with Sch 58261, a considerable reduction in c-fos expression was observed in the ischemic hemispheres, whereas a limited effect was detected in the others. Our results suggest that inhibition of immediate-early gene expression by the A(2A)receptors antagonist Sch 58261 may contribute to its neuroprotective activity.
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PMID:Blockade of A(2A) adenosine receptors leads to c-fos inhibition in a rat model of brain ischemia. 1184 24

Adenosine is considered an endogenous neuroprotective metabolite that through activation of the A(1) receptor results in reduction of neuronal damage following cerebral ischemia. Protein kinase B, also known as Akt/PKB, is part of an endogenous pathway that exerts effective neuroprotection from both necrotic and apoptotic cell death. Using a rat model of unilateral common carotid artery occlusion coupled with hypoxia, and using in vitro rat hippocampal slices, we examined the ability of adenosine to directly activate Akt/PKB. Western blot analysis revealed that levels of phosphorylated Akt/PKB were elevated in vivo under ischemic conditions in an adenosine A(1)-dependent manner and elevated in hippocampal slices treated with an adenosine A(1) agonist. We conclude from these studies that the activation of an adenosine A(1) receptor-mediated signal transduction pathway, either by endogenous adenosine (in vivo) or by an adenosine A(1) agonist (in vitro), results in the activation of the neurotrophic kinase Akt/PKB.
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PMID:Adenosine-mediated activation of Akt/protein kinase B in the rat hippocampus in vitro and in vivo. 1213 82

Adenosine is a neuromodulator known to inhibit the synaptic release of neurotransmitters, e.g., glutamate, and to hyperpolarize postsynaptic neurons. The release of adenosine is markedly enhanced under ischemic conditions. It may then act as an endogenous neuroprotectant against cerebral ischemia and excitotoxic neuronal damage. The mechanisms by which adenosine is released from nervous tissue are not fully known, particularly in the immature brain. We now characterized the release of [3H]adenosine from hippocampal slices from developing (7-day-old) and adult (3-month-old) mice using a superfusion system. The properties of the release differed only partially in the immature and mature hippocampus. The K(+)-evoked release was Ca2+ and Na+ dependent. Anion channels were also involved. Ionotropic glutamate receptor agonists potentiated the release in a receptor-mediated manner. Activation of metabotropic glutamate receptors enhanced the release in developing mice, with group II receptors alone being effective. The evoked adenosine release apparently provides neuroprotective effects against excitotoxicity under cell-damaging conditions. Taurine had no effect on adenosine release in adult mice, but depressed the release concentration dependently in the immature hippocampus.
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PMID:Mechanisms of adenosine release in the developing and adult mouse hippocampus. 1239 2

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A(1) and A(2A) receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A(1) and A(2A) receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices.Slices were superfused with oxygen- and glucose-deprived medium and [(3)H]D-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca(2+) ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [(3)H]D-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor DL-TBOA prevented the ischemia-evoked efflux of [(3)H]D-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [(3)H]D-aspartate or glutamate was increased by the A(1) receptor antagonist DPCPX. The A(2A) antagonist SCH 58261 decreased [(3)H]D-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC(50): 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A(1) or the A(2A) receptor antagonist was found on the ischemia-evoked efflux of [(3)H]D-aspartate in Ca(2+)-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A(1) and stimulatory A(2A) receptors that down- or up-regulate the vesicular-like component of glutamate release.
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PMID:Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. 1284 26


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