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

Blockade of adenosine receptors can reduce cerebral infarct size in the model of global ischaemia. Using the potent and selective A2A adenosine receptor antagonist, SCH 58261, we assessed whether A2A receptors are involved in the neuronal damage following focal cerebral ischaemia as induced by occluding the left middle cerebral artery. SCH 58261 (0.01 mg/kg either i.p. or i.v.) administered to normotensive rats 10 min after ischaemia markedly reduced cortical infarct volume as measured 24 h later (30% vs controls, p < 0.05). Similar effects were observed when SCH 58261 (0.01 mg/kg, i.p.) was administered to hypertensive rats (28% infarct volume reduction vs controls, p < 0.05). Neuroprotective properties of SCH 58261 administered after ischaemia indicate that blockade of A2A adenosine receptors is a potentially useful biological target for the reduction of brain injury.
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PMID:Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. 987 35

Numerous studies have consistently shown that agonist stimulation of adenosine A1 receptors results in a significant reduction of morbidity and mortality associated with global and focal brain ischemia in animals. Based on these observations, several authors have suggested utilization of adenosine A1 receptors as targets for the development of clinically viable drugs against ischemic brain disorders. Recent advent of adenosine A1 receptor agonists characterized by lowered cardiovascular effects added additional strength to this argument. On the other hand, although cardioprotective, adenosine A3 receptor agonists proved severely cerebrodestructive when administered prior to global ischemia in gerbils. Moreover, stimulation of adenosine A3 receptors appears to reduce the efficacy of some of the neuroprotective actions mediated by adenosine A receptors. The review discusses the possible role of adenosine receptor subtypes (A1, A2, and A3) in the context of their involvement in the pathology of cerebral ischemia, and analyzes putative strategies for the development of clinically useful strategies based on adenosine and its receptors. It also stresses the need for further experimental studies before definitive conclusions on the usefulness of the adenosine concept in the treatment of brain ischemia can be made.
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PMID:Adenosine and cerebral ischemia: therapeutic future or death of a brave concept? 1035 98

Numerous studies have consistently shown that agonist stimulation of adenosine A1 receptors results in a significant reduction of morbidity and mortality associated with global and focal brain ischemia in animals. Based on these observations, several authors have suggested utilization of adenosine A1 receptors as targets for the development of clinically viable drugs against ischemic brain disorders. Recent advent of adenosine A1 receptor agonists characterized by lowered cardiovascular effects added additional strength to this argument. On the other hand, although cardioprotective, adenosine A3 receptor agonists proved severely cerebrodestructive when administered prior to global ischemia in gerbils. Moreover, stimulation of adenosine A3 receptors appears to reduce the efficacy of some of the neuroprotective actions mediated by adenosine A1 receptors. The review discusses the possible role of adenosine receptor subtypes (A1, A2, and A3) in the context of their involvement in the pathology of cerebral ischemia, and analyzes putative strategies for the development of clinically useful strategies based on adenosine and its receptors. It also stresses the need for further experimental studies before definitive conclusions on the usefulness of the adenosine concept in the treatment of brain ischemia can be made.
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PMID:Adenosine and cerebral ischemia: therapeutic future or death of a brave concept? 998 18

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

The purpose of this study was to determine the effects of adenosine agonists and an antagonist on ischemia-induced extracellular glutamate concentrations in an animal model of transient cerebral ischemia using in vivo cerebral microdialysis. Fifty New Zealand white rabbits were randomly assigned to one of five groups (normothermia, hypothermia, cyclopentyladenosine (CPA), theophylline, or propentofylline). Microdialysis probes were stereotactically placed in the dorsal hippocampus. Twenty minutes before the onset of ischemia, either 1 mg/kg CPA, 5 mg/kg propentofylline, or 20 mg/kg theophylline were administered intravenously. Esophageal temperature was maintained at 38 degrees C, except in the hypothermic animals, which were cooled to 30 degrees C throughout the entire experiment. Two 12-min periods of cerebral ischemia, separated by a 105-min interval of reperfusion, were produced by inflating a neck tourniquet. High-performance liquid chromatography was used to determine the glutamate concentration in the microdialysate. There were no significant increases in glutamate concentrations during the first ischemic period in any of the five groups. During the second ischemic episode, glutamate concentrations in the normothermic group peaked at levels approximately three times higher than the initial values. A similar pattern of changes in glutamate concentrations was observed in the CPA, propentofylline, and theophylline groups. In the hypothermic group, the concentrations of glutamate remained at baseline levels during the entire experiment. Contrary to expectations, neither the adenosine agonists (CPA, propentofylline) nor the antagonist (theophylline) had any effect on extracellular glutamate concentrations in the peri-ischemic period. Although adenosine and its analogs may be cerebroprotective agents, their mechanism of action is not fully understood. The data derived from this study indicates that the acute administration of such agents had no effect on ischemia-induced glutamate release within the hippocampus under these experimental conditions. Based on these results, further work is needed to compare in vivo versus in vitro experimental results in acute and long-term treatment studies with adenosine receptor agonists and antagonists.
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PMID:Effects of adenosine agonists and an antagonist on excitatory transmitter release from the ischemic rabbit hippocampus. 1092 82

A(3) adenosine receptors have been proposed to play an important role in the pathophysiology of cerebral ischemia with a regimen-dependent nature of the therapeutic effects probably related to receptor desensitization and down-regulation. Here we studied the agonist-induced internalization of human A(3) adenosine receptors in transfected Chinese hamster ovary cells, and then we evaluated the relationship between internalization and signal desensitization and resensitization. Binding of N(6)-(4-amino-3-[(125)I]iodobenzyl)adenosine-5'-N-methyluronamide to membranes from Chinese hamster ovary cells stably transfected with the human A(3) adenosine receptor showed a profile typical of these receptors in other cell lines (K:(D) = 1.3+/-0.08 nM; B(max) = 400+/-28 fmol/mg of proteins). The iodinated agonist, bound at 4 degrees C to whole transfected cells, was internalized by increasing the temperature to 37 degrees C with a rate constant of 0.04+/-0.034 min(-1). Agonist-induced internalization of A(3) adenosine receptors was directly demonstrated by immunogold electron microscopy, which revealed the localization of these receptors in plasma membranes and intracellular vesicles. Moreover, short-term exposure of these cells to the agonist caused rapid desensitization as tested in adenylyl cyclase assays. Subsequent removal of the agonist led to restoration of the receptor function and recycling of the receptors to the cell surface. The rate constant of receptor recycling was 0.02+/-0.0017 min(-1). Blockade of internalization and recycling demonstrated that internalization did not affect signal desensitization, whereas recycling of internalized receptors was implicated in the signal resensitization.
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PMID:Agonist-induced internalization and recycling of the human A(3) adenosine receptors: role in receptor desensitization and resensitization. 1098 29

Selective A(1)adenosine receptor agonists produced a considerable neuroprotective effect during global cerebral ischemia. The neuroprotective effect decreased in the order: A(1)agonists-NECA-adenosine-A(2A)agonist CGS 21680, while selective A(3)adenosine receptor agonist was ineffective. Inhibitory analysis showed that A(1)adenosine receptors mediate the neuroprotective effect of CPA, are involved in the effects of NECA and adenosine (but not CGS 21680), and participate in natural resistance to cerebral ischemia. The role of A(2B)adenosine receptors in the realization of neuroprotective effects was also demonstrated.
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PMID:Role of adenosine receptors in neuroprotective effect during global cerebral ischemia. 1155 51

We investigated how transient cerebral ischemia affects the gene expression, immunoreactive protein levels, and the function of the A1 subtype of adenosine receptor in the rat hippocampus at different times following reperfusion. A1 receptor mRNA levels were altered significantly in different hippocampal subfields as early as 6 h following insult. However, these changes in mRNA levels were not paralleled at the protein level, as western blotting with A1 receptor-specific antibodies revealed that hippocampal A1 adenosine receptor prevalence did not differ from sham control at either 6 or 24 h following insult. The lack of change in A1 receptor prevalence was consistent with functional examinations, as only marginal changes were observed in the ability of A1 receptors to attenuate excitatory post-synaptic potentials in the CA1 subfield at 24 h following reperfusion. These data illustrate that although the mRNA expression levels of the A1 adenosine receptor are altered by transient cerebral ischemia, the immunoreactive prevalence and function of this receptor are maintained in the post-ischemic hippocampus at times preceding the death of the vulnerable neurons.
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PMID:Expression and function of A1 adenosine receptors in the rat hippocampus following transient forebrain ischemia. 1222 May 58

The excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons. The neuromodulator adenosine is known to inhibit the presynaptic release of neurotransmitters and to hyperpolarize postsynaptic neurons in the hippocampus, which would imply that it is an endogenous protective agent against cerebral ischemia and excitotoxic neuronal damage. Interactions of the GABAergic and adenosinergic systems in regulating neuronal excitability in the hippocampus is of crucial importance, particularly under cell-damaging conditions. We now characterized the effects of adenosine receptor agonists and antagonists on the release of preloaded [3H]GABA from hippocampal slices prepared from adult (3-month-old) mice, using a superfusion system. The effects were tested both under normal conditions and in ischemia induced by omitting glucose and oxygen from the superfusion medium. Basal and K+ -evoked GABA release in the hippocampus were depressed by adenosinergic compounds. Under normal conditions activation of both adenosine A1 and A2A receptors by the agonists R(-)N6-(2-phenylisopropyl)adenosine and CGS 21680 inhibited the K+ -evoked release, which effects were blocked by their specific antagonists, 8-cyclopentyl-1,3-dipropyl-xanthine and 3,7-dimethyl-1-propargylxanthine, respectively. Under ischemic conditions the release of both GABA and adenosine is markedly enhanced. The above receptor agonists then depressed both the basal and K+ -evoked GABA release, only the action of A2A receptors being however receptor-mediated. The demonstrated depression of GABA release by adenosine in the hippocampus could be deleterious to neurons and contribute to excitotoxicity.
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PMID:GABA release modified by adenosine receptors in mouse hippocampal slices under normal and ischemic conditions. 1607 17

The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA(3) adenosine receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at the six-position. Many derivatives show high hA(3) adenosine receptor affinities and selectivities both versus hA(1) and hA(2A) receptors. The observed structure-affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (13), which shows high hA(3) affinity (K(i)=5.5nM) and selectivity versus hA(1), hA(2A) (both selectivity ratios>1800) and hA(2B) (cAMP assay, IC(50)>10,000nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in delaying the occurrence of anoxic depolarization.
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PMID:Synthesis, ligand-receptor modeling studies and pharmacological evaluation of novel 4-modified-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent and selective human A3 adenosine receptor antagonists. 1846 46


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