Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the microdialysis technique and laser-Doppler flowmetry, we performed simultaneous measurement of salicylate hydroxylation and glutamate release along with local CBF in the ischemic penumbral cortex of rat brain subjected to normothermic transient middle cerebral artery (MCA) occlusion. Cortical CBF fell to 24 +/- 11% (mean +/- SD) during ischemia and recovered to 84 +/- 16% during reperfusion. Extracellular glutamate levels increased by 6.5-fold above baseline 10 min following MCA occlusion but subsequently returned to near baseline levels in spite of the persistent ischemia. Increase in 2,3- and 2,5-dihydroxybenzoic acid (DHBA) concentrations in the microdialysis perfusate was confirmed during both ischemia and reperfusion phase. Although the temporal profile and amount of salicylate hydroxylation were heterogeneous among individual animals, integrated 2,3-DHBA concentrations during reperfusion were correlated positively with integrated glutamate concentrations during ischemia and negatively with mean postischemic CBF. These relationships suggest a possible association of the enhanced production of 2,3-DHBA during reperfusion with larger amounts of intraischemic glutamate release and lower levels of post-ischemic CBF.
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PMID:Simultaneous measurement of salicylate hydroxylation and glutamate release in the penumbral cortex following transient middle cerebral artery occlusion in rats. 853 May 61

We studied the effects of the aminosteroid U-74389G (21-[4-(2, 6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)- triene-3,20-dione(2)-2-butenenedionate), a putative inhibitor of lipid peroxidation, which protects the rat myocardium after ischemia and reperfusion. Pentobarbital-anesthetized (50 mg/kg) rats were subjected to 60 min of occlusion of the left main coronary artery followed by 60 min of reperfusion. Myocardial ischemia/reperfusion produced a large cardiac necrosis (81 +/- 8.6% of the area at risk and 65 +/- 14.8% of the total left ventricle), polymorphonuclear infiltration in the jeopardized tissue (myeloperoxidase activity = 4.2 +/- 2.1 U X 10(-3)/g tissue in the area at risk and 7.0 +/- 3.6 U X 10(-3)/g tissue in the necrotic area), hydroxyl radical (OH.) formation (0.55 +/- 0.16 nmol/ml), increased plasma malonylaldehyde (40.2 +/- 3.9 nmol/ml) and lactate dehydrogenase (431 +/- 30 mIU/ml) and caused a decrease in the survival rate. Treatment with U-74389G (15 and 30 mg/kg i.v.) at the onset of reperfusion caused a reduction of necrotic area expressed as a percentage of either the area at risk (76 +/-7.4% with 15 mg/kg and 69 +/- 13.5% with 30 mg/kg; P < .05) or the total left ventricle (53 +/- 13.6% with 15 mg/kg and 46 +/- 16.8% with 30 mg/kg; P < .05). Treatment U-74389G reduced the myeloperoxidase activity, evaluated as an index of neutrophil infiltration, both in the area at risk (2.7 +/- 1.1 and 2.2 +/- 1.7 U X 10(-3)/g tissue with the doses of 15 and 30 mg/kg, respectively; P < .05) and in the necrotic area (4.3 +/- 2.4 and 3.8 +/- 2.9 U X 10(-3)/g tissue with 15 and 30 mg/kg, respectively; P < .05); decreased OH. formation (measured indirectly by the administration of the trapping agent salicylic acid); and analyzing the hydroxylation product 2,5-dihydroxybenzoic acid during reperfusion (0.35 +/- 0.12 and 0.32 +/- 0.15 nmol/ml with the doses of 15 and 30 mg/kg, respectively; P < .005). Treatment inhibited lipid peroxidation by blunting plasma malonylaldehyde (26.7 +/- 3.1 and 20.8 +/- 3.3 with the doses of 15 and 30 mg/kg, respectively; P < .001), prevented cellular disruption by reducing the increase of plasma lactate dehydrogenase (288.6 +/- 28 and 201.3 +/- 16 mIU/ml with the doses of 15 and 30 mg/kg, respectively; P < .001). Finally, U-74389G enhanced the survival rate evaluated at the end of the experiment (from 40 to 87%). These outcomes suggest that the drug may have potential for cardioprotective use in acute myocardial infarction.
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PMID:Protection of ischemic and reperfused rat myocardium by the nonglucocorticoid 21-aminosteroid U-74389G, a new inhibitor of lipid peroxidation. 861 38

Preexisting hyperglycemia is associated with enhanced reperfusion injury in the postischemic rat brain. The goal of this study was to evaluate whether the hyperglycemic exacerbation of brain injury is associated with enhanced generation of hydroxyl radicals in rats subjected to middle cerebral artery occlusion (2 h), followed by reperfusion (2 h). Magnetic resonance images revealed the exacerbation of focal brain injury in hyperglycemic rats. The salicylate trapping method was used in conjunction with microdialysis to continuously estimate hydroxyl radical production by measurement of the stable adducts 2,3- and 2,5-dihydroxybenzoic acid (DHBA) during ischemia/reperfusion. In normoglycemic rats, from a mean baseline level of 130 nmol/l, 2,3-DHBA levels surged to peak levels of 194 nmol/l 45 min into ischemia and to 197 nmol/l 15-30 min into the reperfusion period, returning to baseline by 2 h into reperfusion. A similar temporal profile was observed in hyperglycemic rats, except that absolute 2,3-DHBA levels were higher (165 nmol/l at baseline, 317 nmol/l peak during ischemia, 333 nmol/l peak during reperfusion), and levels remained significantly high (p < .05) throughout the reperfusion period. These results suggest that hydroxyl radical is an important contributor to the exacerbation of neuronal and cerebrovascular injury after focal ischemia/reperfusion in hyperglycemic rats.
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PMID:Hydroxyl radical formation in hyperglycemic rats during middle cerebral artery occlusion/reperfusion. 935 41

The purpose of this study was to investigate the mechanisms by which a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), is neuroprotective in the hyperglycemic rat model of 2 h of transient middle cerebral artery occlusion followed by 2 h of reperfusion (MCAO/R). The salicylate trapping method was used in conjunction with a microdialysis technique to continuously estimate hydroxyl radical (.OH) formation by measurement of the stable adducts 2,3- and 2,5-dihydroxybenzoic acid (DHBA). Extracellular excitatory amino acids (EAAs) were detected from the same microdialysis samples. Magnetic resonance imaging (MRI) techniques were used to measure neuronal and cerebrovascular injury. The magnitude of EAA release correlated with the levels of the .OH adducts. Treatment with L-NAME (3 mg/kg, i.p.) 1 min before MCAO, and again 1 min before reperfusion, reduced the levels of DHBA by 46. 4% and glutamate by 50.5% in the hyperglycemic rats compared to untreated hyperglycemic controls. MRI indicated that L-NAME reduced the no-reflow zone and the cytotoxic lesion volume to 22.5% and 21. 0%, respectively, that of hyperglycemic controls. Co-treatment with the nitric oxide (NO) donor L-arginine completely eliminated the protective effects of l-NAME with respect to .OH and EAA levels as well as MRI lesion volume. Our data suggest that hyperglycemic MCAO/R results in excessive glutamate excitotoxicity, leading to enhanced generation of .OH via a NO-mediated mechanism, in turn resulting in severe ischemia/reperfusion brain injury.
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PMID:Effect of nitric oxide synthase inhibitor on a hyperglycemic rat model of reversible focal ischemia: detection of excitatory amino acids release and hydroxyl radical formation. 959 67

This study sought to determine whether gallium-desferrioxamine (Ga/DFO) can curb free radical formation and mitigate biochemical and electrophysiological parameters of injury in the cat retina subjected to ischemia followed by reperfusion. For the biochemical studies, cat eyes were subjected to 90 min of retinal ischemia followed by 5 min of reperfusion, and enucleation of one eye of each cat was used to measure retinal reperfusion injury. Before enucleation of fellow eyes, 2.5 mg/kg Ga/DFO was injected intravenously 5 min before reperfusion. The flux of hydroxyl radicals, as measured directly by conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid (2,3- and 2,5-DHBA), was significantly lower in Ga/DFO-treated eyes. The mean normalized level of 2,3-DHBA (considered a specific marker of hydroxyl radicals) was 3.5 times higher in untreated eyes. Ga/DFO caused a significant reduction, by 2.56-fold, in lipid peroxidation, as reflected by levels of malondialdehyde. Ascorbic acid, a natural antioxidant present in the retina, is severely depleted in untreated eyes. In contrast, in Ga/DFO-treated eyes, levels were 10 times higher than the control. Energy charge was 2.38 times higher in treated eyes. Levels of purine catabolites (hypoxanthine, xanthine, and uric acid) that reflect excessive metabolism of purine nucleotides were approximately twice higher in untreated retinas. Electroretionographic studies, performed on a different subset of animals, substantiated the biochemical results. In Ga/DFO-treated eyes the amplitude of the mixed cone-rod response b-wave (as compared with fellow nonischemic eyes) fully recovered within 24 h after ischemia (b-wave ratio 1.04 +/- 0.09, [mean +/- SEM]) whereas ischemic/reperfused and nontreated eyes recovered to only 0.33 +/- 0. 05. The results show that severe biochemical and functional retinal injury occurs in cat eyes subjected to ischemia and reperfusion. These severe changes were significantly reduced by a single administration of Ga/DFO just before reperfusion. We hypothesize that the protection afforded by Ga/DFO is due to a combined effect of "Push-Pull" mechanisms interfering with transition metal-dependent and free radical-mediated injurious processes.
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PMID:Gallium-desferrioxamine protects the cat retina against injury after ischemia and reperfusion. 1069 41

The present study used isolated rat hearts to investigate whether (1) Sheng-Mei-San (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, is protective against post-ischemic myocardial dysfunction, and (2) whether the cardioprotective effect of SMS is related to scavenging of hydroxyl radicals and opening the mitochondrial KATP channels. The excised hearts of male Sprague-Dawley rats were perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. Left ventricular end-diastolic pressure (LVEDP, mmHg), left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30-min pre-ischemic period followed by a 30-min global ischemia and 60-min reperfusion. Lactate, lactate dehydrogenase (LDH) and 2,5-dihydroxybenzoic acid (2,5-DHBA) concentrations in the effluent were measured during reperfusion. Three days' treatment with SMS (1.67 ml/kg per day) inhibited the rise in LVEDP and improved the post-ischemic LVDP and +/-dP/dt significantly better than in the untreated control hearts during reperfusion. SMS increased the coronary flow at baseline, and during reperfusion. Pretreatment with 5-hydroxydecanoic acid (5-HD), a mitochondrial KATP channel blocker, abolished the inhibition of the rise in LVEDP, the increase in coronary flow and the improvement in LVDP and +/-dP/dt induced by SMS. SMS significantly attenuated the concentrations of lactate, LDH and 2,5-DHBA during reperfusion, but the pretreatment with 5-HD restored them; 5-HD alone did not affect the concentrations. SMS improved the post-ischemic myocardial dysfunction through opening the mitochondrial KATP channels.
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PMID:Sheng-Mai-San is protective against post-ischemic myocardial dysfunction in rats through its opening of the mitochondrial KATP channels. 1219 3

Flupirtine is a triaminopyridine derived centrally acting analgetic, which has been found to display neuroprotective effects in models of excitotoxic cell damage, global, and focal ischemia, but no direct interaction with any component of the N-methyl-D-aspartate (NMDA) and glutamate triggered Ca(2+)-channel. Additionally flupirtine shows potent antioxidant effects in isolated mitochondria and cell culture. Work in models of monoamine depletion and neuroleptic induced catalepsy in rats suggests a interaction of flupirtine with the dopaminergic neurotransmitter system as well. This prompted us to examine the effect of flupirtine on methamphetamine toxicity in mice and to investigate the influence on dopamine release and free radical formation in the rat striatum by microdialysis that may explain methamphetamine neurotoxicity. Pretreatment of C57-BL mice with flupirtine (4 x 10 mg/kg) significantly attenuated the striatal dopamine loss after methamphetamine application (4 x 5 mg/kg). In rats, a single injection of 10 mg/kg flupirtine reduced the methamphetamine induced striatal dopamine release by almost 50%, as measured by in vivo microdialysis. Flupirtine, however, did not influence the increase of free radical formation after methamphetamine infusion, which was assayed after infusion of salicylic acid by quantification of 2,3- and 2,5-dihydroxybenzoic acid. This suggests that other mechanisms rather than dopamine metabolism and autoxidation, may contribute to methamphetamine neurotoxicity.
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PMID:Attenuation of methamphetamine induced dopaminergic neurotoxicity by flupirtine: microdialysis study on dopamine release and free radical generation. 1258 76

This study examined whether quinaprilat, an angiotensin-converting enzyme inhibitor, reduces the infarct size, and investigated the mechanisms for its infarct size-reducing effect, in rabbits. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Quinaprilat (100 microg/kg/h or 300 microg/kg/h for 70 min, IV) was administered 20 min before ischemia with or without pretreatment with Nomega-nitro-l-arginine methyl ester (l-NAME) (10 mg/kg, IV, a nitric oxide synthase inhibitor), 5-hydroxydecanoic acid sodium salt (5-HD) or posttreatment with 5-HD (5 mg/kg, IV, a mitochondrial KATP channel blocker). The area at risk as a percentage of the left ventricle was determined by Evans blue dye and the infarct size was determined as a percent of the area at risk by triphenyl tetrazolium chloride staining. Using a microdialysis technique, myocardial interstitial levels of 2,5-dihydroxybenzoic acid (2,5-DHBA), an indicator of hydroxyl radicals, and NOx, an indicator of nitric oxide, were measured before, during, and after 30 min of ischemia. Quinaprilat significantly reduced the infarct size in a dose-dependent manner (30.1 +/- 3%, n = 10, and 27.6 +/- 2%, n = 7, respectively) compared with the control (46.5 +/- 4%, n = 10). The infarct size-reducing effect of quinaprilat was completely blocked by pretreatment with l-NAME (43.8 +/- 2%, n = 8) and 5-HD (50.1 +/- 3%, n = 8) and posttreatment with 5-HD (50.3 +/- 2%, n = 8), respectively. Quinaprilat did not affect the myocardial interstitial 2,5-DHBA level but significantly increased the NOx level during ischemia and reperfusion. Quinaprilat reduces myocardial infarct size involving NO production and mitochondrial KATP channels in rabbits without collateral circulation.
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PMID:Quinaprilat reduces myocardial infarct size involving nitric oxide production and mitochondrial KATP channel in rabbits. 1277 74

A small reduction of body temperature during reperfusion following cerebral ischemia has been known to ameliorate neuronal injury. However, the mechanisms underlying postischemic hypothermia-induced neuroprotection are poorly understood. The burst of reactive oxygen species (ROS) formation that occurs during reperfusion has been documented to be involved in ischemic neuronal degeneration. In this study, we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 min in male Wistar rats. The body temperature was kept at 37 degrees C during ischemia and controlled at either 32 degrees C or 37 degrees C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2,3- and 2,5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine, while determining striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37 degrees C, the levels of 2,3- and 2,5-DHBA significantly increased after reperfusion. The peak levels of 2,3- and 2,5- DHBA were 2.9-fold and 2.7-fold increased above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.
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PMID:Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats. 1280 82

There is evidence that the excessive generation of reactive oxygen free radicals contributes to the brain injury associated with cerebral ischemia. In the present study, the protective effect of chronic administration of ethyl docosahexaenoate (E-DHA) against oxidative brain injury was evaluated in the gerbil model of transient cerebral ischemia. Weanling male gerbils were orally pretreated with either E-DHA (200 mg/kg) or vehicle, once a day, for 10 weeks and subjected to bilateral occlusion of common carotid arteries for 10 min. At the different reperfusion times, E-DHA pretreatment significantly inhibited the increases in the production of brain salicylate-derived 2,5-dihydroxybenzoic acid (2,5-DHBA) and content of brain malonildialdehyde (MDA). The superoxide dismutase (SOD) activity was not modified; however, pretreatment with E-DHA significantly prevented the level of brain-reduced glutathione (GSH) and activities of brain glutathione peroxidase (GSH-P(X)) and catalase (CAT) from declines caused by cerebral ischemia. Moreover, ischemia and reperfusion-induced delayed neuronal loss in the hippocampus CA1 sector and locomotor hyperactivity were also significantly attenuated by pretreatment with E-DHA. These results suggested that the neuroprotective effect of E-DHA might be due to its antioxidant property.
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PMID:Protective effect of chronic ethyl docosahexaenoate administration on brain injury in ischemic gerbils. 1558 73


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