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)

Cerebral ischemia of 5 min duration was induced in unanesthetized Mongolian gerbils by bilateral occlusion of the carotid arteries. The extent of ischemic injury was assessed behaviorally by measuring the increases in locomotor activity following ischemia and by a histopathological assessment of the extent of CA1 hippocampal pyramidal cell injury and loss 5 days after ischemia. The A2a adenosine receptor selective antagonists 8-(3-chlorostyryl) caffeine (CSC; 0.1 mg/kg i.p.) and 4-amino-1-phenyl[1,2,4]-triazolo[4,3-a] quinoxaline (CP 66,713; 0.1 mg/kg i.p.) reduced the extent of ischemia-induced injury. An A1 selective receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1.0 mg/kg i.p.), enhanced ischemia-evoked injury. These results suggest that adenosine A2a receptor antagonists may be useful for the prevention of cerebral injuries resulting from stroke or cardiac arrest.
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PMID:The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil. 882 36

We have used thapsigargin (TG), a specific, irreversible inhibitor of endoplasmic reticulum (ER) Ca(2+)-ATPases, and caffeine, an agonist of the ryanodine receptor, to study the effect of emptying of ER calcium stores on protein synthesis in neuronal cells. TG at 1 microM caused a permanent inhibition of protein synthesis in hippocampal slices from 3-week-old rats but no inhibition in slices prepared from 2-month-old animals. Caffeine at 10 mM caused a reduction of protein synthesis in both 3-week- and 2-month-old rats immediately after exposure, but complete recovery of protein synthesis occurred within 30 min after treatment. In neuronal cells, TG produced an almost complete inhibition of protein synthesis that was only partially reversed over a 24-h recovery period. TG did not significantly affect neuronal ATP levels or energy charge. Fifty percent inhibition of protein synthesis was achieved with approximately 5 nM TG. Recovery of protein synthesis after TG treatment was significantly hindered when serum was omitted from the medium after TG exposure, suggesting that serum promotes recovery of ER calcium homeostasis. It is concluded that TG is a suitable tool for the study of the mechanisms of protein synthesis inhibition after transient cerebral ischemia. The possibility that disturbances in ER calcium homeostasis may contribute to the pathological process of ischemic cell death is discussed.
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PMID:Depletion of neuronal endoplasmic reticulum calcium stores by thapsigargin: effect on protein synthesis. 885 60

Despite significant progress in understanding of the potential of adenosine A1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A2 receptors in the regulation of cerebral blood flow, we have investigated the effect of both acute and chronic administration of the selective adenosine receptor agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N- ethylcarboxoamidoadenosine (APEC) and antagonist 8-(3-chlorostyryl)caffeine (CSC) on the outcome of 10 min ischemia in gerbils. Acute treatment with APEC improved recovery of postischemic blood flow and survival without affecting neuronal preservation in the hippocampus. Acute treatment with CSC had no effect on the cerebral blood flow but resulted in a very significant protection of hippocampal neurons. Significant improvement of survival was present during the initial 10 days postischemia. Due to subsequent deaths of animals treated acutely with CSC, the end-point mortality (14 days postischemia) in this group did not differ statistically from that seen in the controls. It is, however, possible that the late mortality in the acute CSC group was caused by the systemic effects of brain ischemia that are not subject to the treatment with this drug. Chronic treatment with APEC resulted in a statistically significant improvement in all studied measures. Although chronic treatment with CSC improved postischemic blood flow, its effect on neuronal preservation was minimal and statistically insignificant. Mortality remained unaffected. The results indicate that the acute treatment with adenosine A2A receptor antagonists may have a limited value in treatment of global ischemia. However, since administered CSC has no effect on the reestablishment of postischemic blood flow, treatment of stroke with adenosine A2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.
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PMID:Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist. 899 4

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

Cerebral ischaemia was induced in anaesthetized rats by occlusion of the ipsilateral common carotid and middle cerebral arteries. The response to ischaemia was assessed by the reduction of the amplitude of recorded somatosensory evoked potentials (SSEPs), and the rate of recovery of the SSEPs during reperfusion. Caffeine and pentoxifylline when applied at 70 mM to the cortex for 60 min prior to induction of ischaemia significantly reduced the ischaemia induced attenuation of the SSEPs and hastened recovery to control levels. In contrast, application of normal saline or of the drugs for 15 min did not reduce the effect of ischaemia on the SSEPs. These results suggest that caffeine and pentoxifylline have potential roles in the management of patients with cerebral ischaemia.
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PMID:Neuroprotection by caffeine and pentoxifylline during experimental cerebral ischaemia. 1037 87

We examined the effect of ischemia on inositol 1,4,5-trisphosphate receptor-induced Ca2+ release by functional and morphological approaches, using the gerbil model after 6-h unilateral occlusion of the common carotid artery. Autoradiographic study revealed that the basal uptake of 45Ca2+ into the endoplasmic reticulum and caffeine-induced 45Ca2+ release from the endoplasmic reticulum were normal in the presence of ATP in each ischemic brain region, whereas inositol 1,4,5-trisphosphate receptor-induced 45Ca2+ release from the endoplasmic reticulum was inhibited only in the CA1 region of the hippocampus on the ischemic side. In moderately ischemic gerbils, electron microscopic study demonstrated aggregation of swollen endoplasmic reticulum in the CA1 region of the hippocampus, so that abundant endoplasmic reticulum assembled in close contact to form endoplasmic reticulum cisternal stacks. In severely ischemic gerbils, immunohistochemical analysis of the hippocampus showed loss of type 1 inositol 1,4,5-trisphosphate receptor protein with preservation of immunoreactivity for type 2 and 3 inositol 1,4,5-trisphosphate receptor proteins, which was confirmed by western blot analysis. Such selective inhibition of inositol 1,4,5-trisphosphate receptor-induced Ca2+ release and the loss of type 1 inositol 1,4,5-trisphosphate receptor in the CA1 region of the hippocampus in cerebral ischemia may be associated with its region-specific vulnerability to ischemia.
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PMID:Selective inhibition of inositol 1,4,5-triphosphate-induced Ca2+ release in the CA1 region of the hippocampus in the ischemic gerbil. 1047 64

Caffeine and ethanol are two commonly overused psychoactive dietary components. The purpose of this study was to assess the effects of acute, chronic, oral (p.o.) and intravenous (i.v.) caffeine, ethanol and their combination on infarct volume following focal ischemia in rats. Rats received treatment either p.o. 3 h and 1 h before, or by i.v. infusion for 2.5 h beginning 30-180 min after, ischemia. There were six acute treatment groups. (1) oral dH2O (control); (2) oral caffeine (10 mg/kg); (3) oral ethanol (0.65 g/kg total); (4) oral ethanol plus caffeine; (5) intravenous saline; and (6) intravenous ethanol (0.65 g/kg) plus caffeine (10 mg/kg) in saline. A 7th group received oral ethanol plus caffeine for three weeks prior to ischemia. After 3 h of left MCA/CCA occlusion and 24 h reperfusion, infarct volume was determined. Control animal infarct volume was 102.4+/-42.0 mm3. Oral caffeine alone had no effect (122.4+/-30.2 mm3). Oral ethanol alone exacerbated infarct volume (177.2+/-27.8 mm3). Oral caffeine plus ethanol almost entirely eliminated the damage (17.89+/-10.41 mm3). When i.v. treatment with ethanol plus caffeine was initiated at 30, 60, 90 and 120 minutes post-ischemia the infarct volume was reduced by 71.7%, 49.8%, 64.8% and 47.1%, respectively. Chronic daily oral ethanol plus caffeine prior to ischemia eliminated the neuroprotection seen with acute treatment. These studies indicate that ethanol, which by itself aggravates cerebral ischemia, and caffeine, when combined together immediately before or for 2 h after focal stroke, reduces ischemic damage.
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PMID:Combination of low dose ethanol and caffeine protects brain from damage produced by focal ischemia in rats. 1069 17

The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells. The explanation that the drug abrogates the G2 block and shortens repair in G2 by promoting early entry into mitosis is not anymore tenable because enhancement of radiotoxicity requires presence of the drug during irradiation and fails when the drug is added after irradiation at the G2 maximum. Repair assays by measurement of recovery ratios and by delayed plating experiments indeed strongly suggested a role in repair which is now confirmed for Pentoxifylline by constant field gel electrophoresis (CFGE) measurements and for Pentoxifylline and for Caffeine by use of a variety of repair mutants. The picture now emerging shows that Caffeine and Pentoxifylline inhibit homologous recombination by targeting members of the PIK kinase family (ATM and ATR) which facilitate repair in G2. Pentoxifylline induced repair inhibition between irradiation dose fractions to counter interfraction repair has been successfully applied in a model for stereotactic surgery. Another realistic avenue of application of Pentoxifylline in tumour therapy comes from experiments which show that repair events in G2 can be targeted directly by addition of cytotoxic drugs and Pentoxifylline at the G2 maximum. Under these conditions massive dose enhancement factors of up to 80 have been observed suggesting that it may be possible to realise dramatic improvements to tumour growth control in the clinic.
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PMID:Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives. 1459 74

Disturbances in neuronal calcium homeostasis have been implicated in a variety of neuropathological conditions, including cerebral ischemia, hypoglycemia, and epilepsy, and possibly constitute part of the cell death process associated with chronic neurodegenerative disorders. We investigated if endoplasmic reticulum (ER) calcium stores participate in neuronal death triggered by moderate glycolysis inhibition induced by iodoacetate, an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, in cultured hippocampal neurons. Results show that exposure to iodoacetate leads to a slow partial decrease in cell survival, which is significantly prevented in the absence of Ca(2+) or in the presence of the calcium chelator BAPTA-AM. Treatment with caffeine and a low (1 microM) concentration of ryanodine, which activates the ryanodine receptor (RyR), exacerbates neuronal death, whereas dantrolene and 25 microM ryanodine, which antagonizes RyR, prevents damage. Xestospongin C (XeC), an antagonist of the inositol-3-phosphate (IP(3)) receptor (IP(3)R) also prevents neuronal damage. Inhibitors of the ER calcium ATPase (sarcoendoplasmic reticulum Ca(2+) ATPase; SERCA) have no effect. The decrease in ATP levels induced by iodoacetate is potentiated by caffeine and prevented by dantrolene. Although only a slight increase in glutamate extracellular levels is observed 3.5 hr after iodoacetate exposure, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, MK-801, efficiently prevents neuronal damage. Taken together, the data suggest that neuronal death induced during moderate glycolysis inhibition involves calcium influx through NMDA receptors and calcium release from intracellular ER stores. These results might be relevant to the understanding the mechanisms involved in neuronal damage related to aging and chronic neurodegenerative diseases, which have been associated with decreased glucose metabolism.
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PMID:Disruption of endoplasmic reticulum calcium stores is involved in neuronal death induced by glycolysis inhibition in cultured hippocampal neurons. 1617 70

Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and anti-inflammatory properties.
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PMID:Beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral ischemia-reperfusion injury in rats. 2382 80


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