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)

We investigated the ability of N6-cyclohexyladenosine (CHA), a potent and selective agonist of the adenosine A1 receptor, to attenuate elevations of levels of extracellular hippocampal glutamate and glycine that result from episodes of transient global cerebral ischemia (TGCI). A total of 30 New Zealand white rabbits were randomly assigned to receive 0 (n = 5), 0.1 (n = 8), 1.0 (n = 6), 10 (n = 6), or 100 (n = 5) microM CHA. The drug was dissolved in artificial CSF (vehicle) and administered via a microdialysis probe placed stereotactically into the dorsal hippocampus. A second microdialysis probe placed into the contralateral hippocampus of each animal was perfused with vehicle alone. Ten minutes of TGCI was induced by neck tourniquet inflation and deliberate hypotension from 0 to 10 min. Microdialysis samples were collected as follows: every 20 min preischemia (at -80, -60, -40, -20, and 0 min); every 5 min during ischemia and in the immediate reperfusion period (at 5, 10, 15, and 20 min); and every 20 min for the remainder of the reperfusion period (at 40, 60, and 80 min). Samples were then analyzed for their concentration of glutamate and glycine by HPLC. Following 10 min of ischemia, glutamate levels increased to a peak of 3.28 +/- 0.55 times baseline and returned to preischemic levels by 40 min, i.e., during reperfusion. Glycine concentrations increased to 5.41 +/- 0.91 times over baseline and remained elevated for the duration of the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of cyclohexyladenosine on the periischemic increases of hippocampal glutamate and glycine in the rabbit. 135 2

Basic neuroscience research findings during the past five years have established a clear relationship between the excitatory amino acid (EAA) neurotransmitters (glutamic and aspartic acid) and various pathological states. A major mechanism of neural tissue degeneration following cerebral ischemia, and perhaps other neurodegenerative diseases, seems to involve overactivity of the EAA system in brain. This process is called delayed excitotoxicity and it has become a focal point for the design of new drugs that inhibit its course (EAA receptor blockers). Very recently it has been shown that it is possible to block delayed excitotoxicity using adenosine A1 receptor agonists which inhibit EAA release pre-synaptically. This approach is very effective in reducing post-stroke neurological damage in a number of animal models and has certain advantages when compared to the EAA receptor blocker strategy. Adenosine agonists not only inhibit excitotoxicity but they also block granulocyte activation and the capillary no-reflow phenomenon which results. An additional adenosinergic approach involves brain permeable adenosine uptake blockers which would serve to increase adenosine levels somewhat selectively at ischemic foci thereby inhibiting EAA release. The adenosinergic approach to stroke therapeutics may be a potentially effective strategy for new drug development in neurology, and may have general applicability to other neurodegenerative disease states where excitotoxicity is being implicated.
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PMID:Adenosinergic approaches to stroke therapeutics. 197 12

The purpose of this study was to evaluate potential mechanisms of ischemia-evoked amino acid transmitter release. Changes in extracellular levels of transmitter amino acids and lactic acid dehydrogenase (LDH) in rat cerebral cortex during and following four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked release of glutamate, aspartate and gamma-amino-butyric acid (GABA) was compared in control vs. drug-treated animals. Tetrodotoxin and antagonists of glutamate receptors (DNQX, MK-801, and AP-3) depressed the initial rate of increase in extracellular glutamate and aspartate without altering the total amount of these amino acids collected in the cortical superfusates. Cobalt, a calcium channel antagonist, failed to alter efflux. Acidic amino acid transport inhibitors (dihydrokainate, L-trans-PDC) depressed the rate of onset of glutamate and aspartate release and dihydrokainate depressed total release by 44%. PD 81723, an allosteric enhancer at the A1 adenosine receptor, depressed glutamate efflux, as did L-NAME, an inhibitor of nitric oxide synthase. Extracellular increases in GABA levels were depressed by tetrodotoxin and L-trans-PDC. The GABA transport inhibitor, nipecotic acid, increased the initial rate of onset of GABA release. Increases in LDH levels in the extracellular fluid became apparent during the period of ischemia and continued to increase during the subsequent 90 min of reperfusion. These results suggest that ischemia evokes a release of neurotransmitter amino acids that is only partially dependent upon Ca2+ influx activation or the reversal of amino acid transporters. Nonselective mechanisms, resulting from the disruption of plasma membrane integrity, may contribute significantly to the total ischemia-evoked release of excitatory amino acids.
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PMID:Characterization of glutamate, aspartate, and GABA release from ischemic rat cerebral cortex. 791 62

The effects of AMG-1 [6(5-hydroxy-2-methylpyridylamino)-9 ribofranosylpurine], an adenosine analogue, and adenosine on Ca2+-dependent and independent release of glutamate from rat synaptosomes induced by KCl 30 mmol.L-1 were studied with an enzyme-linked fluorometric assay. The synaptosomes were prepared and preincubated for 30 min at 37 degrees C. Two ml of incubation mixture containing synaptosomes (1.27 mg protein), NADP+ 1 mmol.L-1, L-glutamic dehydrogenase 50 U, CaCl2 1.3 mmol.L-1 (or EGTA 1.3 mmol.L-1) was transferred to the stirred cuvette in the fluorometer at 37 degrees C for 5 min. Then, AMG-1 (or adenosine) was added. Released glutamate (eg. fluorescent intensity) was monitored following the addition of 30 mmol.L-1 KCl. The results indicate that Ca2+-dependent glutamate release from depolarized synaptosomes is inhibited by AMG-1 (0.1 mmol.L-1) or adenosine (0.3 mmol.L-1). The action of AMG-1 seems to be similar to that of adenosine. However, no change was found on Ca2+-independent release of glutamate. This implies that the protective effect of AMG-1 against cerebral ischemia may be partially due to inhibiting glutamate release from nerve terminal via the activation of adenosine A1 receptor.
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PMID:[Effect of AMG-1 and adenosine on glutamate release from synaptosomes in rats]. 803 Apr 10

The effect of chronic administration of selective adenosine A1 receptor agonists and antagonists on the outcome of cerebral ischemia is entirely unknown. Therefore, we have investigated the impact of such regimens on the hippocampal adenosine A1 receptor density, and on the recovery from 10 min forebrain ischemia in gerbils. While acutely administered N6-cyclopentyladenosine (CPA) given at 0.02 mg/kg resulted only in a significant reduction of mortality, at 1 mg/kg it improved both survival and neuronal preservation in the hippocampal CA1 region. Acute treatment with 1,3-dipropyl-8-cyclopentylxanthine (CPX) significantly worsened the outcome and enhanced neuronal destruction. The effects of chronic administration of these drugs (15 days followed by 1 drug-free day) were opposite. Thus, although chronic CPA at 0.02 mg/kg did not have any effect at all, at 1 mg/kg both survival and neuronal preservation were significantly poorer than in controls, while chronic CPX resulted in a significant improvement of both measures. These results were not accompanied by adenosine A1 receptor up- or downregulation. Our study indicates that highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well.
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PMID:Chronic administration of selective adenosine A1 receptor agonist or antagonist in cerebral ischemia. 805 Apr 67

1. The adenosine A1 receptor enhancer, PD 81,723, was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion cerebral ischemia. 2. Gerbils were injected with PD 81,723 (1, 10 and 125 mg/kg i.p.) 20 min before a 5-min episode of forebrain ischemia. The extent of ischemic injury was assessed by monitoring the increases in locomotor activity and from the degree of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. 3. By both criteria, PD 81,723, at all three dose levels, failed to protect against ischemia/reperfusion evoked cerebral injury.
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PMID:Adenosine A1 receptor enhancer, PD 81,723, and cerebral ischemia/reperfusion injury in the gerbil. 869 Feb 43

Agonists of adenosine A1 receptors have been frequently proposed as candidates for clinical development in treatment of cerebral ischemia and stroke. Numerous experimental studies have shown that pre- and postischemic administration of these drugs results in a very significant reduction of postischemic brain damage. However, only a few studies determined the impact of cerebral ischemia and drug treatment on postischemic recovery of spatial memory. The present paper demonstrates that preischemic i.p. administration of adenosine amine congener (ADAC) at 100 micrograms/kg in gerbils results in a significant (P < 0.05) reduction of postischemic mortality and hippocampal, cortical and striatal morbidity. Postischemic Morris' water maze tests show that preischemic treatment with ADAC also leads to a very significant (P < 0.001) reduction of postischemic spatial memory loss. Our results indicate feasibility of further consideration of adenosine A1 receptor agonists as a clinically applicable acute treatment of brain ischemia. Recent development of neuroprotective adenosine A1 receptor agonists that are free of cardiovascular side effects supports such development.
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PMID:Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. 879 Sep 90

Although adenosine receptor-based treatment of cerebral ischemia and other neurodegenerative disorders has been frequently advocated, cardiovascular side effects and an uncertain therapeutic time window of such treatment have constituted major obstacles to clinical implementation. Therefore, we have investigated the neuroprotective effects of the adenosine A1 receptor agonist adenosine amine congener (ADAC) injected after either 5 or 10 min ischemia at 100 micrograms/kg. When the drug was administered at either 6 or 12 h following 5 min forebrain ischemia, all animals were still alive on the 14th day after the occlusion. In both ADAC treated groups neuronal survival was approximately 85% vs. 50% in controls. Administration of a single dose of ADAC at times 15 min to 12 h after 10 min ischemia resulted in a significant improvement of survival in animals injected either at 15 or 30 min, or at 1, 2, or 3 h after the insult. In all 10 min ischemia groups, administration of ADAC resulted in a significant protection of neuronal morphology and preservation of microtubule associated protein 2 (MAP-2). However, postischemic Morris' water maze tests revealed full preservation of spatial memory and learning ability in animals injected at 6 h. On the other hand, the performance of gerbils treated at 12 h postischemia was indistinguishable from that of the controls. Administration of ADAC at 100 micrograms/kg in non-ischemic animals did not result in bradycardia, hypotension, or hypothermia. The data indicate that when ADAC is used postischemically, the most optimal level of protection is obtained when drugs are given at 30 min to 6 h after the insult. Although the mechanisms involved in neuroprotective effects of adenosine A1 receptor agonists require further studies, the present results demonstrate the feasibility of their clinical applications.
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PMID:Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils. 898 84

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

The inhibitory neuromodulator adenosine is neuroprotective against damage induced by cerebral ischemia. Its vasodilator effects add to its suitability as a possible anti-stroke agent, but also account for unwanted side effects following systemic administration of adenosine receptor agonists. ATP breakdown during ischemia produces adenosine which effluxes out of the neuron. This review will focus on endogenously produced adenosine and its subsequent protection against ischemia-induced neuronal damage in some stroke models, but will also highlight possible disadvantages to increasing adenosine concentrations. In the advantages column, therapeutic benefits have been obtained by enhancing synaptic concentrations of endogenous adenosine using the adenosine uptake inhibitor propentofylline, but not dipyridamole. There is an emerging role for endogenous adenosine in preventing delayed cell death, e.g. following hypoxic pre-conditioning. One of the cons associated with enhancing the synaptic concentration of adenosine is the appearance of adenosine receptor desensitization over time. Thus, there is a therapeutic window of opportunity during which activation of an adenosine A1 receptor is beneficial to an ischemic neuron.
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PMID:Neuroprotective effects of adenosine in cerebral ischemia: window of opportunity. 906 44


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