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)

Regional cerebral ischemia was produced in 18 Java monkeys by permanent middle cerebral artery (MCA) occlusion. All monkeys were thereafter paralyzed (pancuronium bromide, 0.05 mg/kg/hr) and sedated (diazepam, 0.1 mg/kg/hr) for a 48-hour period. Thirty minutes after MCA occlusion, pentobarbital sodium anesthesia was induced in nine of the monkeys (14 mg/kg) and maintained for 48 hours (7 mg/kg every two hours), with continuous supportive care. After 48 hours, all drugs were discontinued; the monkeys were observed for five days, and then killed. Seven of the control monkeys developed a cerebral infarction, three did not survive past the 48 hours of intensive care, and the other four had a notable neurologic deficit. All pentobarbital monkeys survived the seven days, but four had a cerebral infarction and two of these had a notable neurologic deficit. These differences were statistically significant.
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PMID:Cerebral protection by barbiturate anesthesia. Use after middle cerebral artery occlusion in Java monkeys. 81 99

The development of fluorocarbon-based oxygen carriers has experienced rapid progress over the past few years. Fluosol has been approved for use during percutaneous transluminal coronary angioplasty (PTCA) for high-risk patients. Its clinical evaluation is being pursued as an adjunct to cancer therapy and for treatment of myocardial infarction in conjunction with thrombolytic therapy. O2-delivery efficacy has been achieved with the development of the new highly concentrated (4 to 5 times more concentrated than Fluosol), fluid, emulsions of perfluorooctyl bromide (perflubron), trade-named Oxygen. The stability of fluorocarbon emulsions has also improved considerably and the new emulsions can be stored unfrozen and are ready for use. The side-effect profile of these emulsions has been characterized as being the normal response of the body's phagocytes to the injection of particles, a response that is considered physiological rather than pathological in nature; it involves some products of arachidonic acid metabolism and can be controlled pharmacologically. Means of further stabilizing fluorocarbon emulsions, involving molecular-diffusion-controlling additives or fluorinated surfactants, including mixed fluorocarbon-hydrocarbon compounds, have been devised. Increased control over in vivo particle recognition, intravascular persistence and side effects, and at adapting emulsion characteristics to specific applications, is being investigated. The range of therapeutic applications is expanding. The concentrated emulsions will be able to serve as a temporary red blood cell substitute in many situations. Acute normovolemic hemodilution with fluorocarbon emulsions, used in conjunction with homologous predonation and other blood-sparing techniques, should afford greater flexibility, increase the margin of safety, and reduce or alleviate the need for autologous blood transfusion during surgical procedures. Fluorocarbon applications in the cardiovascular field include use during PTCA, for cardioplegia and reperfusion, and the treatment of myocardial infarction. Significant tumor growth delay has been achieved when concentrated emulsions are used in conjunction with cancer radio- or chemotherapy. Liquid ventilation has potential as a unique treatment for the adult and infant respiratory distress syndromes and for drug delivery. The radiopaque and versatile perflubron can also be used in contrast agents for diagnosis with computed X-ray tomography, magnetic resonance imaging and ultrasound, allowing the early detection and staging of cancer. Other potential applications investigated include the treatment of cerebral ischemia, organ and limb preservation, use as a tamponade during retinal repair, etc.
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PMID:Overview of progress in the fluorocarbon approach to in vivo oxygen delivery. 139 34

An ion-pair reversed phase high performance liquid chromatographic method was developed for the quantitative determination of lipoperoxide (as malondialdehyde, MDA) in animal tissue using a ODS column and a mobile phase of methanol + phosphate buffer (53:47 v/v, pH 6.5). Tetrabutylammonium bromide was used as an ion-pair reagent and the detection wavelength was set at 532 nm. The method was sensitive, accurate and simple. A linear relationship was obtained between the peak height and the amount of MDA from 50 nmol/L to 1200 nmol/L and the lower limit of detection of MDA was 15 nmol/L (signal-to-noise ratio greater than 2), and the coefficient of variation at the 200 nmol/L level was 3.7% (n = 7). The results correlated well with those from the 2-thiobarbituric acid colorimetric method. The method has been used in the pathogenic studies of cerebral ischemia and acute renal failure for the determination of trace lipoperoxide.
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PMID:Determination of lipoperoxide in animal tissue by ion-pair reversed phase high performance liquid chromatography. 227 45

Swelling of astrocytes in the brain is a major cause of the morbidity and mortality associated with stroke and head trauma. Using a human astrocytoma cell line (UC-11MG) as a model system, we studied cell volume changes caused by ATP depletion under conditions mimicking hypoxia. ATP levels were reduced to less than 10% of control using the metabolic inhibitors KCN or antimycin in combination with glucose deprivation. This was sufficient to eliminate ouabain-sensitive 86Rb+ uptake, indicating the Na+-K+-adenosinetriphosphatase was not operating. Furosemide-sensitive 86Rb+ uptake was reduced by approximately 60%, indicating Na+-K+-2Cl- cotransport was also sensitive to ATP loss. ATP depletion resulted in a 30-40% reduction of cell volume within 60 min. ATP depletion also resulted in a net loss of intracellular K+. This loss of K+ could be blocked by Ba2+, indicating the K+ loss was through a conductive channel. When the net K+ loss was blocked by Ba2+, the volume decrease was also prevented. The cells remained viable throughout the time period as judged by exclusion of ethidium bromide by 99% of the cells and recovery of ATP levels to 75% of control within 60 min. We conclude that ATP depletion, following inhibition of glycolysis and oxidative phosphorylation, causes astrocytes to shrink because of a more rapid loss of K+ than uptake of Na+. Thus it appears that ATP depletion alone is not sufficient to account for the rapid phase of astrocytic swelling observed during cerebral ischemia.
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PMID:Energy-dependent cell volume maintenance in UC-11MG human astrocytomas. 280 31

Elevated levels of glutamate and aspartate have been implicated in the pathogenesis of neural injury and death induced by ischemia. The mechanism(s) whereby they escape into the extracellular environment have been a subject of controversy. This study evaluated the contribution of phospholipases and protein kinases to ischemia-evoked glutamate and aspartate release from the ischemic/reperfused rat cerebral cortex. Changes in the extracellular levels of these amino acids during four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked amino acid release was compared in control vs. drug treated animals, in which selective inhibitors of phospholipases and protein kinases were applied topically onto the cerebral cortex. The phospholipase inhibitors tested included 4-bromophenacyl bromide, a non-selective inhibitor; 7,7-dimethyleicosadienoic (DEDA), an inhibitor of secretory type phospholipase A2 (PLA2); AACOCF3, an inhibitor of the Ca2(+)-dependent cytoplasmic form of PLA2, HELSS, which inhibits a Ca(2+)-independent cytoplasmic PLA2, and U73122, a selective inhibitor of phospholipase C (PLC). All five phospholipase inhibitors significantly attenuated glutamate and aspartate release into the extracellular milieu, indicating the possibility that several forms of the enzyme are likely to be involved. The protein kinase C (PKC) inhibitor, chelerythrine chloride, also reduced excitatory amino acid efflux, wheres the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced their release. The non-selective kinase inhibitor, staurosporine, and H-89, which selectively inhibits protein kinase A, did not reduce ischemia-evoked amino acid efflux. These results suggest that ischemia-evoked release of the excitatory transmitters amino acids is a result, in part, of the activation of phospholipases A2 and C, with PKC involvement in the transduction process. Destabilization and deterioration of the plasma membrane, as a consequence of phospholipid hydrolysis, may allow these transmitter amino acids to diffuse down their concentration gradients into the extracellular fluid.
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PMID:Mechanisms of glutamate and aspartate release in the ischemic rat cerebral cortex. 888 99

Induction of chemical anoxia, using sodium azide in cerebellar granule cells maintained in primary culture, was evaluated as an in vitro assay for screening of potential neuroprotective compounds. The purpose of this study was to evaluate sodium azide as an alternative to cyanide salts, compounds which, despite their unfavorable characteristics, are often used in assays for chemical anoxia. The viability of neuronal cultures after treatment with azide, with or without preincubation with calcium channel blockers, tetrodotoxin (TTX), or glutamate receptor antagonists, was monitored by subsequent incubation with the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), followed by isopropanol extraction and spectrophotometric quantification of cellularly reduced MTT. The azide-induced degeneration of neurons was shown to be dependent on the concentration as well as on the duration of incubation with submaximal concentrations of azide. Incubation of the neurons with nifedipine, a blocker of L-type voltage-sensitive calcium channels (L-VSCC), or with the noncompetitive N-methyl-D-aspartate (NMDA) subtype glutamate receptor antagonist MK-801, prior to addition of submaximal concentrations of azide, significantly attenuated azide-induced neuronal death. Blockers of N-type and Q-type VSCC (omega-conotoxin MVIIA and MVIIC, respectively) and the P-type VSCC blocker omega-agatoxin IVA had no effect in this assay. The sodium channel blocker TTX was without effect when added to neurons under depolarizing conditions, but potently and effectively protected cells when experiments were performed in a nondepolarizing buffer. The results show that chemical anoxia induced by incubation of cultured neurons with azide leads to detrimental effects, which may be quantitatively monitored by the capability of the cells to reduce MTT. This procedure is a suitable method for screening of compounds for possible protective effects against neuronal death induced by energy depletion. In addition, the results suggest involvement of L-type VSCC as well as of glutamate receptors in the pathways leading to neuronal degradation induced by energy depletion in cerebellar granule neurons. This would further support the notion that these pathways might be important in neurodegeneration induced by cerebral ischemia or anoxia.
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PMID:Characterization of a chemical anoxia model in cerebellar granule neurons using sodium azide: protection by nifedipine and MK-801. 892 28

The mechanisms of ischemic cell damage are still not fully understood. It has been shown that alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)/kainate receptor antagonists, such as 6-nitro-7- sulphamoyl-benzo-(f)-quinoxaline-2, 3-dione (NBQX), are neuroprotective in models of transient forebrain ischemia, even when applied during recovery, indicating that nonNMDA receptors may play a pivotal role in ischemic cell damage. In the present series of experiments, we studied whether transient cerebral ischemia causes changes in the extent of mRNA editing of AMPA/kainate receptor subunits, a reaction critical for the control of calcium flux through nonNMDA receptor ion channels. Transient cerebral ischemia was produced in rats using the four-vessel occlusion (4-VO) model. After 30 min of ischemia, brains were recirculated for 4, 8, or 24 h. Total RNA was extracted from the cortex, striatum, and hippocampus in order to analyze the extent of mRNA editing of the glutamate receptor subunits GluR2, GluR5, and GluR6. RNA was converted by reverse transcription into cDNA, which was used as a template for subunit-specific polymerase chain reaction (PCR) to amplify a product across the edited base A (A edited to I in the second transmembrane-spanning regions of GluR2, GluR5, and GluR6). PCR products were analyzed with the restriction enzyme Bbv 1, which recognizes the cDNA sequence GCAGC originating from unedited but not that originating from edited GluR2, GluR5, or GluR6 mRNA (GCGGC, the base I is read as G). Restriction digests were electrophoresed, and the bands visualized with ethidium bromide and then photographed. The extent of mRNA editing of the different subunits was quantified using image analysis and appropriate standards. In all control brains studied, GluR2 mRNA was completely edited and remained so after reversible cerebral ischemia. The extent of GluR5 mRNA editing was significantly upregulated in the striatum (from 39 +/- 6% in controls to 57 +/- 9 and 56 +/- 7 after 4 and 8 h of recovery, respectively, p < 0.05 versus control) but not in the cortex and hippocampus. The extent of GluR6 mRNA editing was significantly reduced after 24 h of recovery: in the cortex, from 92 +/- 1 to 78 +/- 6% (p < 0.01); in the striatum, from 91 +/- 2 to 79 +/- 1% (p < 0.001); and in the hippocampus, from 90 +/- 3 to 80 +/- 2% (p < 0.05). A significant reduction was already apparent in the striatum after 4 h of recovery (p < 0.05). Results indicate that mRNA editing is regulated differently in each of the glutamate receptor subunits GluR2, GluR5, and GluR6 after transient cerebral ischemia. The ischemia-induced upregulation of GluR5 mRNA editing observed in the striatum may be indicative of a higher sensitivity to transient ischemia of neurons that exhibit a large fraction of unedited GluR5 mRNA. This assumption is corroborated by the observation (Mackler and Eberwine, 1993) that GluR5 mRNA is completely unedited in neurons of the hippocampal CA1-subfield, a region most vulnerable to transient cerebral ischemia. Whether the decrease in GluR6 mRNA editing observed in all brain structures after ischemia results from a disturbance of the editing reaction or from glial proliferation will have to be established in further experiments. Studying ischemia-induced changes in mRNA editing of glutamate receptor subunits GluR5 and GluR6 may help to elucidate the molecular mechanisms of ischemic cell damage.
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PMID:RNA editing of glutamate receptor subunits GluR2, GluR5 and GluR6 in transient cerebral ischemia in the rat. 896 93

Recent studies have shown that the novel antioxidant LY231617 protects against ischaemia-induced neuronal damage in rat models of global cerebral ischaemia. In the present studies we have examined the effects of LY231617 in the gerbil model of global cerebral ischaemia. We also examined the effects of four nitric oxide synthase inhibitors (3-bromo-7-nitroindazole, N(G)-nitro-L-arginine methyl ester, aminoguanidine and S-methylisothiourea sulphate) in this model. LY231617 (50 mg/kg p.o. or 30 mg/kg i.p.) was administered either 30 min prior to occlusion or immediately post-occlusion followed by three further doses at 4, 24 and 48 h after the initial dose. 3-Bromo-7-nitroindazole was administered at 40 mg/kg i.p. immediately after occlusion followed by 20 mg/kg i.p. at 3, 6, 24 and 48 h, N(G)-nitro-L-arginine methyl ester was administered at 10 mg/kg i.p. immediately after occlusion followed by 5 mg/kg i.p. at 3, 6, 24 and 48 h. Aminoguanidine was administered at 80 mg/kg i.p. immediately after occlusion followed by 40 mg/kg i.p. at 3, 6, 24 and 48 h and S-methylisothiourea sulphate was administered at 10 mg/kg i.p. immediately, 3, 6, 24 and 48 h after occlusion. We also examined the effects of aminoguanidine administered at 80 mg/kg i.p. immediately after occlusion followed by 40 mg/kg i.p. at 3, 6, 24, 48, 72 and 96 h and S-methylisothiourea sulphate administered at 10 mg/kg i.p. immediately, 3, 6, 24, 48, 72 and 96 h after occlusion. Control animals were either sham operated or subjected to 5 min bilateral carotid occlusion. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5-min bilateral carotid artery occluded animals 5 days after surgery. LY231617 provided significant neuroprotection against the ischaemia-induced brain damage when administration was initiated before or after occlusion (P < 0.05). The neuronal NO synthase inhibitors, 3-bromo-7-nitroindazole and a general NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester also provided significant neuroprotection (P < 0.05). In contrast aminoguanidine and S-methylisothiourea sulphate (two inducible NO synthase inhibitors) failed to protect against the ischaemia-induced brain damage. These results indicate that free radicals and nitric oxide are involved in ischaemia-induced brain damage following global cerebral ischaemia. Antioxidants such as LY231617 or neuronal NO synthase inhibitors can prevent the ischaemia-induced neurodegeneration and may be useful as anti-ischaemic agents.
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PMID:Neuroprotective effects of the antioxidant LY231617 and NO synthase inhibitors in global cerebral ischaemia. 923 32

Free radical-induced lipid peroxidation is an important factor in the pathogenesis of ischemic brain damage. We studied the effects of the alpha-tocopherol analogue MDL 74,722 on iron-dependent lipid peroxidation and infarct volume after transient focal cerebral ischemia. The effects of MDL 74,722 on iron-induced lipid peroxidation were tested in cerebellar granule cell cultures by means of a thiobarbituric acid reactive substances (TBARS) assay. The absorbance resulting from mitochondrial reduction of 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was taken as a measure of cell viability. Besides, in male Wistar rats the left middle cerebral artery (MCA) was occluded for 3 h by means of an intraluminal filament. Rats were treated with vehicle (n = 19) or MDL 74,722 (n = 17), administered intravenously for 3 h in a dose of 2 mg/(kg.h), starting 105 min after MCA occlusion. Infarct volume was measured in coronal brain sections stained with hematoxylin and eosin. In cerebellar granule cell cultures, MDL 74,722 resulted in a dose-dependent inhibition of TBARS formation and prevention of cell toxicity. The compound reduced infarct volume after transient occlusion of the MCA in rats by 49%. It is concluded that MDL 74,722 is a potent inhibitor of lipid peroxidation and reduces infarct volume by about one half, even when treatment is delayed. This contributes to its potential clinical usefulness.
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PMID:Inhibition of iron-dependent and ischemia-induced brain damage by the alpha-tocopherol analogue MDL 74,722. 991 9

This study was designed to determine the role of altered cAMP and K(+) channel-dependent mechanisms in impaired pial artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ) following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Recent studies have observed that NOC/oFQ elicits pial dilation via release of cAMP, which, in turn, activates the calcium sensitive (K(ca)) and the ATP-dependent K(+) (K(ATP)) channel. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased pO(2) to 35+/-3 mm Hg with unchanged pCO(2). Topical NOC/oFQ (10(-8), 10(-6) M) induced vasodilation was attenuated by ischemia/reperfusion (I+R) and reversed to vasoconstriction by hypoxia/ischemia/reperfusion (H+I+R) at 1 h of reperfusion (control, 9+/-1 and 16+/-1%; I+R, 3+/-1 and 6+/-1%; H+I+R, -7+/-1 and -12+/-1%). Such altered dilation returned to control values within 4 h in I+R animals and within 12 h in H+I+R animals. NOC/oFQ dilation was associated with elevated CSF cAMP in control animals but such biochemical changes were attenuated in I+R animals and reversed to decreases in cAMP concentration in H+I+R animals (control, 1037+/-58 and 1919+/-209 fmol/ml; I+R, 1068+/-33 and 1289+/-30 fmol/ml; H+I+R, 976+/-36 and 772+/-27 fmol/ml for absence and presence of NOC/oFQ 10(-6) M, respectively). Topical 8-Bromo cAMP (10(-8), 10(-6) M) pial dilation was unchanged by I+R but blunted by H+I+R (control, 10+/-1 and 20+/-1%; I+R, 11+/-1 and 20+/-2%; H+I+R, 0+/-1 and 0+/-2%). Pituitary adenylate cyclase activating polypeptide and cromakalim, adenylate cyclase and K(ATP) channel activators, respectively, elicited dilation that was blunted by both I+R and H+I+R while NS1619, a K(ca) channel activator, elicited dilation that was unchanged by I+R but blunted by H+I+R. These data indicate that impaired NOC/oFQ dilation following I+R results form altered adenylate cyclase and K(ATP) channel-dependent mechanisms. These data further indicate that impaired NOC/oFQ dilation following H+I+R results not only from altered adenylate cyclase and K(ATP) channel but also from altered cAMP and K(ca) channel-dependent mechanisms.
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PMID:Role of cAMP and K(+) channel-dependent mechanisms in piglet hypoxic/ischemic impaired nociceptin/orphanin FQ-induced cerebrovasodilation. 1108 86


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