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

Alterations of [3H]cyclic AMP (cAMP) binding, an indicator of the binding activity of particulate cyclic AMP-dependent protein kinase (PKA), were examined after 15 and 30 min of ischemia in the gerbil brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. Significant reductions in cAMP binding were noted only in the dendritic subfields of the hippocampus CA1 such as the strata oriens, radiatum and lacunosum-moleculare, on the ischemic side after 15 min of ischemia. After 30 min ischemia cAMP binding was significantly decreased not only in each dendritic subfield of the hippocampus CA1, but also in the layer of pyramidal cell bodies (stratum pyramidale) on the occluded side; other brain regions such as the hippocampus CA3, dentate gyrus and cerebral cortices revealed no significant changes in cAMP binding. These findings suggest that derangement of PKA may begin in the dendritic subfields of the hippocampus CA1 after as little as 15 min of severe ischemia, and proceed centrally to the neuronal cell bodies of the hippocampus CA1.
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PMID:Acute ischemic vulnerability of PKA in the dendritic subfields of the hippocampus CA1. 926 2

1. Previous studies have shown that flupirtine, a centrally acting, non-opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of flupirtine, we investigated whether flupirtine is able to modulate potassium or NMDA-induced currents in rat cultured hippocampal neurones by use of the whole-cell configuration of the patch-clamp technique. 2. We demonstrated that 1 microM flupirtine activated an inwardly rectifying potassium current (K(ir)) in hippocampal neurones (deltaI=-39+/-18 pA at -130 mV; n=10). This effect was dose-dependent (EC50=0.6 microM). The reversal potential for K(ir) was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that K(ir) was predominantly carried by K+. Furthermore, the induced current was blocked completely by Ba2+ (1 mM), an effect typical for K(ir). 3. The activation of K(ir) by flupirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism (deltaI=-3+/-6 pA at -130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of K(ir) (n=7). 4. The selective alpha2-adrenoceptor antagonist SKF-86466 (10 microM), the selective 5-HT1A antagonist NAN 190 as well as the selective GABA(B) antagonist 2-hydroxysaclofen (10 microM) failed to block the flupirtine effect on the inward rectifier. 5. Flupirtine (1 microM) could not change the current induced by 50 microM NMDA. 6. These results show that in cultured hippocampal neurones flupirtine activates an inwardly rectifying potassium current and that a PTX-sensitive G-protein is involved in the transduction mechanism.
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PMID:Influence of flupirtine on a G-protein coupled inwardly rectifying potassium current in hippocampal neurones. 942 Dec 79

Different times of incomplete cerebral ischemia (2, 4, 6, 8, 10 and 30 min) were induced by bilateral common carotid artery occlusion in anesthetized rats to evaluate the time course of changes in lipid peroxidation and energy metabolism. Analysis of malondialdehyde (used to assess the levels of lipid peroxidation), ascorbic acid, oxypurines, nucleosides, nicotinic coenzymes and high-energy phosphates, was carried out by high-performance liquid chromatography on neutralized perchloric acid extract of brain tissue. Under the present experimental conditions, malondialdehyde, nicotinic coenzymes and ATP catabolites (oxypurines and nucleosides) were affected by increasing times of ischemia, with respect to control sham-operated rats. In particular, the concentration of malondialdehyde, undetectable in control brains, increased from 1.26 nmol/g wet weight after 2 min of carotid clamping to 13.42 nmol/g wet weight at the end of 30 min of incomplete cerebral ischemia. The presence of oxidative stress was further supported by ascorbic acid depletion, which was particularly significant after 10 and 30 min of incomplete ischemia. Carotid clamping provoked an imbalance between energy production and consumption that was evidenced by a reduction in ATP and GTP concentrations and an increase in ATP degradation products such as AMP, oxypurines and nucleosides. A decrement in the sum of adenine nucleotides and the energy charge potential indicated a progressive malfunctioning of energy-producing metabolic cycles. A possible contribution to such a severe change in energy state might be related to depletion of NAD and NADP, particularly noticeable after the longest incomplete brain ischemia times, that should have provoked a consequent lessening of oxido-reductive reactions. Bilateral carotid clamping causes a significant reduction in brain oxygen and substrate supply that results in inhibition of energy metabolism and triggering of oxygen-radical-induced lipid peroxidation.
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PMID:Effects of increasing times of incomplete cerebral ischemia upon the energy state and lipid peroxidation in the rat. 943 8

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

Selective adenosine receptor agonists and antagonists have marked effects on the outcome of cerebral ischemia, and adenosine receptors are expressed on astrocytes. In this study we examined the effects of various adenosine receptor agonists on the production of nitric oxide and the induction of iNOS in astrocytes activated by LPS/IFN-gamma and TNF-alpha/IL-1beta and on the production of TNF-alpha. Treatment of the cells with the A2A receptor agonist CGS 21680 inhibited both NO production and iNOS expression induced by stimulation with either LPS/IFN-gamma or TNF-alpha/IL-1beta, whereas the A1 and A3 receptor agonists, CPA and Cl-IB-MECA, respectively, did not have significant inhibitory effects. The inhibitory effect of the A2A receptor agonist was antagonized by the specific A2A receptor antagonist CSC. The A2A agonist also exerted a small inhibitory effect on the production of TNF-alpha. Similar inhibitory effects on the production of NO were obtained by cyclic AMP-elevating reagents, such as forskolin and dibutyryl cyclic AMP. Our findings suggest that activation of the A2A receptor inhibits NO production and iNOS expression likely via increased cAMP.
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PMID:Activation of the A2A adenosine receptor inhibits nitric oxide production in glial cells. 965 May 77

Inflammatory mediators secreted by activated leukocytes play a role in the pathogenesis of atherosclerosis. They may also affect the production of vasodilatory and platelet antiaggregatory factors such as nitric oxide (NO) and prostacyclin (PGI2) from the vascular endothelium. Production of NO and PGI2, the effecs of which are mediated by cyclic 3',5'-guanosine monophosphate (cGMP) and cyclic 3',5'-adenosine monophosphate (cAMP), respectively, is disturbed in atherosclerosis, whereas increased NO levels have been found in acute cerebral ischemia. To investigate leukocyte activation and its possible influence upon endothelial function in cerebral ischemia we measured plasma neutrophil gelatinase-associated lipocalin (NGAL) and soluble tumor necrosis factor receptor protein-1 (sTNFR-1) by ELISA, and intraplatelet cAMP and cGMP by radioimmunoassay in 59 patients with acute ischemic stroke or transient ischemic attack (mean age 71 years, 27 males) and after a 1-year follow-up in 57/59 (97%) patients. NGAL (152 +/- 58 vs. 126 +/- 48 microgram/l), sTNFR-1 (3.50 +/- 2.2 vs. 2.59 +/- 1.31 microgram/l), and cAMP (5.12 +/- 1.71 vs. 4.06 +/- 0.92 pmol/10(9) platelets) were higher (p < 0.001) after follow-up than in acute cerebral ischemia. At follow-up sTNFR-1 and cGMP partially correlated (r = 0.31; p < 0.05), controlling for age and platelet count. In conclusion, plasma NGAL and sTNFR-1 and intraplatelet AMP increase after acute cerebral ischemia, indicating chronic inflammatory activity and endothelial activation. Plasma sTNFR-1 levels are related to intraplatelet cGMP levels.
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PMID:Increasing levels of leukocyte-derived inflammatory mediators in plasma and cAMP in platelets during follow-up after acute cerebral ischemia. 977 47

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.
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PMID:Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats. 979 31

The present study investigates the interrelation between cerebral energy metabolism and memory capacities after acute and permanent occlusions of carotid and vertebral arteries in adult Wistar rats (n=60). Tissue ATP, phosphocreatine, ADP, AMP and adenosine concentrations were determined in rat brain by high-pressure liquid chromatography (HPLC) analysis. Lactate and pyruvate were measured spectrophotometrically. Rats underwent psychometric testing by means of a holeboard test, closed field activity, and passive avoidance behaviour. Acute cerebral ischaemia was associated with a substantial deficit in energy load (-50%). Cortical adenosine and lactate exhibited a 7- and a 10-fold increase, respectively, in concentration. After 2 weeks of four-vessel occlusion, cortical ATP and phosphocreatine showed a partial enhancement in their concentrations if compared with acute ischaemia. Consequently, energy load (micromol/g) increased from 0.59 to 1.42 in cerebral cortex and from 0.58 to 1.14 in hippocampus under conditions of acute and permanent ischaemia, respectively. While lactate was normalized, adenosine showed a 2-fold increase in its cortical concentration. All animals improved their abilities in learning, memory and cognition after a 7-day training period. Acute vessel occlusion severely decreased working memory (WM), reference memory (RM) and locomotor activity. Simultaneously, the passive avoidance test showed a significant reduction in latency time from 247+/-85 s (sham) to 145+/-132 s. The partial improvement in brain energy state was accompanied by a relative improvement in WM and RM, although both memory capacities remained significantly lower than in controls. The data of the present study demonstrate a linear relationship between cerebral energy metabolism and brain memory capacities after acute and permanent vessel occlusions in rats.
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PMID:Interrelation between cerebral energy metabolism and behaviour in a rat model of permanent brain vessel occlusion. 1036 89

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase is an essential step in cyclic AMP-mediated intracellular signal transduction. In the present study, the binding capacity of cyclic AMP-dependent protein kinase for cyclic AMP was examined by autoradiography with local cerebral blood flow in focal cerebral ischemia in the rat, which was induced by occlusion of the middle cerebral artery using the intraluminal suture method. The binding capacity of cyclic AMP-dependent protein kinase and local cerebral blood flow were assessed by the in vitro [3H]cyclic AMP binding and the [14C]iodoantipyrine methods, respectively. At 3 h of occlusion, a significant reduction in the binding of cyclic AMP-dependent protein kinase to cyclic AMP was already noted in the lateral region of the caudate-putamen and the parietal cortex. Between three and five hours of occlusion, the area with reduced cyclic AMP binding was significantly expanded to the peri-ischemic regions including the frontal cortex and the medial region of the caudate-putamen. The threshold in local cerebral blood flow for reduced cyclic AMP binding was clearly noted at 5 h of ischemia, and was 45 ml/100 g per min in the cerebral cortices, and 38 ml/100 g per min in the caudate-putamen, respectively. No threshold was noted at 3 h of ischemia, since cyclic AMP binding showed a large variation ranging from reduced to normal values even when local cerebral blood flow was below 20 ml/100 g per min. Recirculation for 3.5 h following 1.5 h of ischemia restored the normal cyclic AMP binding in the cerebral cortices, but failed to normalize cyclic AMP binding in the caudate-putamen despite good recovery of local cerebral blood flow. Western blot analysis suggested that this reduction in cyclic AMP binding was not due to loss or degradation of the subunit protein of cyclic AMP-dependent protein kinase, and may therefore have resulted from conformational changes in the protein. A significant increase in cyclic AMP binding was noted after recirculation in the non-ischemic regions such as the frontal and the cingulate cortices on the occluded side and in the contralateral cortices. These data indicate that cyclic AMP-mediated signal transduction in the brain tissue may be very susceptible to ischemic stress, and the region of disrupted signal transduction may expand progressively from the ischemic core to peri-ischemic regions in the acute phase of ischemia. Such impairment of signal transduction may not be restored in the caudate-putamen even when cerebral circulation is fully recovered after short-term ischemia, suggesting that a regional vulnerability to ischemic stress may also exist in cyclic AMP-mediated signal transduction. A significant increase in cyclic AMP binding after recirculation in regions outside of ischemic area may be closely related with the protective mechanisms of brain tissue, since cyclic AMP has been reported to exert various neuroprotective actions.
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PMID:Inhibition of cyclic AMP-dependent protein kinase in the acute phase of focal cerebral ischemia in the rat. 1057

NS-7 is a novel blocker of voltage-sensitive Ca(2+) and Na(+) channels, and it significantly reduces infarct size after occlusion of the middle cerebral artery. Persistent activation of cyclic AMP response element binding protein (CREB), which can be induced by increase in intracellular Ca(2+) concentrations or other second messengers, has recently been found to be closely associated with neuronal survival in cerebral ischemia. The present study was therefore undertaken to evaluate the neuroprotective effects of NS-7 by analyzing changes in CREB phosphorylation in a focal cerebral ischemia model. CREB phosphorylation in the brain of rats was investigated immunohistochemically at 3.5-48-h recirculation after 1. 5-h occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was intravenously injected 5 min after the start of recirculation. The NS-7 group showed significantly milder activation of CREB phosphorylation in various cortical regions after 3.5 h of recirculation than the saline group. The inner border zone of ischemia in the NS-7 group subsequently exhibited a moderate, but persistent, increase in number of phosphorylated CREB-positive neurons with no apparent histological damage. By contrast, the saline group displayed a marked, but only transient, increase in number of immunopositive neurons in this border zone after 3.5 h of recirculation, and this was followed by clear suppression of CREB phosphorylation and subsequent loss of normal neurons. These findings suggest that: (1) the marked enhancement of CREB phosphorylation in the acute post-ischemic phase may be triggered largely by an influx of calcium ions as a result of activation of the voltage-sensitive Ca(2+) and Na(+) channels; and that (2) the neuroprotective effects of NS-7 may be accompanied by persistent activation of CREB phosphorylation in the inner border zone of ischemia.
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PMID:Effects of blockade of voltage-sensitive Ca(2+)/Na(+) channels by a novel phenylpyrimidine derivative, NS-7, on CREB phosphorylation in focal cerebral ischemia in the rat. 1091 13


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