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)

Gradient-refocused echo-planar magnetic resonance (MR) images (TE = 18 msec) were acquired in rats during bolus injection of iron oxide particles, and the first pass of the contrast agent through the brain was monitored. In control rats, contrast agent (0.1 mmol/kg iron) produced significant signal-intensity (SI) reduction over the right hemisphere and similar declines over the left. SI loss occurred first in the cortex and basal ganglia and later in the periventricular regions, along the midline, and in the thalamic zone. Sequential volume-localized proton spectra acquired during transit of 0.02 mmol/kg iron showed substantial reduction in SI, slight asymmetric broadening, and no change in chemical shift of the water resonance. In rats with unilateral occlusion of the middle cerebral artery, peak reduction in ischemic brain SI was to 70% +/- 9% of control, while normal brain SI was reduced to 18% +/- 2% (P less than .01), allowing distinction of the ischemic regions. The presence and location of injury were confirmed with diffusion-weighted imaging and postmortem vital staining. These results demonstrate abnormal transit profiles in a rat model of regional brain ischemia. Evaluation of dynamic contrast delivery patterns may provide unique information in early brain ischemia.
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PMID:Detection with echo-planar MR imaging of transit of susceptibility contrast medium in a rat model of regional brain ischemia. 180 41

Iron-mediated peroxidation of brain lipids is known to occur during reperfusion following cardiac arrest. Since in vitro damage to DNA is caused by similar iron-dependent peroxidation, we tested whether free radical damage to genomic DNA also develops during reperfusion following cardiac arrest and resuscitation. Genomic DNA was isolated from the cerebral cortex in (i) normal dogs, (ii) dogs subjected to a 20-min cardiac arrest, and (iii) dogs resuscitated from a 20-min cardiac arrest and then allowed to reperfuse for 2 or 8 h. DNA strand nicks were evaluated by in vitro labeling of newly created 3' and 5' termini. DNA base damage was evaluated utilizing reaction with piperidine prior to labeling of 5' termini. The 3' DNA termini were labeled before and after digestion with exonuclease III, and the 5' DNA termini were labeled before and after treatment with piperidine. In vitro experiments with genomic DNA damaged by oxygen radicals verified that these labeling methods identified radical damage. In the experimental animal groups, terminal incorporation and electrophoretic mobility of brain nuclear DNA are not significantly changed either by 20 min of complete brain ischemia or during the first 8 h of reperfusion. We conclude that genomic DNA is not extensively damaged during cardiac arrest and early reperfusion, and therefore such DNA damage does not appear to be an important early aspect of the neurologic injury that accompanies cardiac arrest and resuscitation.
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PMID:Brain nuclear DNA survives cardiac arrest and reperfusion. 184 65

A major mechanism leading to ischemic damage is loss of cellular ion homeostasis. Energy failure with shortage of ATP is responsible for presynaptic release of glutamate, which then triggers rapid cellular efflux of K+, and influx of Ca2+, Na+, and Cl-, with osmotically obligated water. The neuronal damage occurring in ischemia is probably secondary to the influx of Ca2+, and/or to the intracellular release of Ca2+, with the subsequent activation of proteases and lipases. A delayed form of ischemic damage, observed after transient ischemia, may be caused by increased calcium cycling across metabolically perturbed membranes. Another type of damage, typically leading to pan-necrosis (infarction), seems related to excessive acidosis and to production of free radicals. The mechanisms may involve release of pro-oxidant iron-catalyzed free radical reactions. It has been proposed that free radical damage may preferentially affect microvessels, predisposing to vasogenic edema.
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PMID:The biochemical basis of ischemic brain lesions. 185 97

Several feasible mechanisms have been proposed as sources of neuronal damage from ischemia and subsequent reperfusion. Included among these are oxidative damage caused by free radical production and lipid peroxidation and products derived from phospholipid breakdown. A series of 4-thiazolidinone compounds represented by LY178002 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinon e) have been described as inhibitors of multiple enzymes in the arachidonic acid cascade, including fatty acid cyclooxygenase, 5-lipoxygenase, and phospholipase A2. Accordingly, we evaluated LY178002 in a four-vessel occlusion model of global forebrain ischemia with reperfusion. A 2-hour pretreatment of 11 male Wistar rats with 150 mg/kg LY178002 significantly protected against striatal (p = 0.0007) and hippocampal CA1 (p = 0.006) damage after 30 minutes of global ischemia. Similar protection was observed for the striatum (p = 0.005) and hippocampal CA1 layer (p = 0.025) after pretreatment of 13 rats with 50 mg/kg LY178002. We further evaluated LY178002 as a possible inhibitor of lipid peroxidation because part of its chemical structure incorporates the aromatic backbone of the known antioxidant butylated hydroxytoluene. We found LY178002 to be a potent inhibitor of iron-dependent lipid peroxidation. Few substances possessing a single pharmacological activity have been found to be of significant therapeutic benefit in global ischemia of 30 minutes' duration because the mechanisms that lead to cell death in response to ischemia are likely to be multifactorial. Thus, the efficacy of LY178002 in this model may be due to its ability to inhibit multiple sources of damage.
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PMID:LY178002 reduces rat brain damage after transient global forebrain ischemia. 186 52

It is generally thought that the oxidative modification of hemoproteins leads to their inactivation. In the current study, however, a transiently activated form of myoglobin was shown to be formed when the prosthetic heme group became covalently bound to the polypeptide during the reaction of myoglobin with low levels of HOOH. In the presence of an enzymatic metmyoglobin reducing system containing diaphorase and methylene blue with excess NADH, this HOOH-altered myoglobin catalyzed NADH oxidation and oxygen consumption; the overall stoichiometry indicated a two-electron reduction of oxygen to HOOH. This reaction was not catalyzed by iron released from heme, as desferrioxamine had no effect on the activity. Stoichiometric amounts of HOOH were sufficient to produce the activated oxidase state of myoglobin, whereas larger amounts of HOOH lead to heme destruction, iron release, and inactivation of the oxidase activity. The alteration of myoglobin to an enzyme that can form toxic oxygen metabolites may have pathological importance, especially in myocardial injury caused by ischemia and reperfusion, where myoglobin is present in large amounts and HOOH is formed. Furthermore, the oxidase form may be involved in the mechanism of destruction of the heme seen with oxidative treatment of myoglobin.
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PMID:Oxidative modification by low levels of HOOH can transform myoglobin to an oxidase. 187 Nov 23

Possible roles for iron in coronary artery disease (CAD) have emerged, including contributions to atherogenesis and/or the vulnerability of the myocardium to ischemia/reperfusion events. The value of hepatic storage iron as a potential risk factor for CAD was evaluated independently and in combination with various lipoprotein indices using CAD mortality data from 11 countries along with available data on liver iron stores. CAD mortality rates were found to be best correlated with the liver iron-serum cholesterol product in both men (r = 0.72) and, more importantly, in both genders combined (r = 0.74). It was also found that estimated CAD incidence could be related in a non-linear fashion to iron-cholesterol values in a simple normal distribution model where all subjects above a threshold value of iron-cholesterol were assumed to have CAD. Hepatic iron values thus appear to be useful in describing the differences in CAD due to both diet (and/or culture) and sex.
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PMID:Iron stores and the international variation in mortality from coronary artery disease. 189 Sep 83

We superimposed extreme hypercapnia (arterial Pco2 400-450 mmHg) immediately before and during incomplete cerebral ischemia to distinguish the role of intracellular pH (pHi) and bicarbonate [( HCO3-]i) in postischemic metabolic and electrophysiological recovery. Incomplete global ischemia was produced in seven anesthetized dogs by 30 min of intracranial hypertension followed by 4 h of reperfusion. ATP, phosphocreatine (PCr), and pHi were measured with 31P magnetic resonance spectroscopy, and [HCO3-]i was calculated from the Henderson-Hasselbalch equation using the measured pHi and sagittal sinus Pco2. Cerebral blood flow was reduced to 7 +/- 1 ml.min-1.100 g-1 (+/- SE) during ischemia with extreme hypercapnia, and pHi decreased to 5.72 +/- 0.09. During normocapnic reperfusion, pHi rapidly returned to near baseline values by 14 min. [HCO3-]i fell from 12.1 +/- 0.9 to 6.0 +/- 1.2 mM by the midpoint of ischemia and recovered by 30 min of reperfusion. ATP, PCr, and O2 consumption also recovered rapidly and completely. Somatosensory-evoked potentials (SEP) recovered to 43 +/- 10% of control amplitude. These results are in marked contrast to the poor metabolic and SEP recovery previously observed in hyperglycemic dogs in which pHi decreased to the same range as with hypercapnic ischemia, but in which [HCO3-]i was much lower (1.1 +/- 0.5 mM). Therefore, [HCO3-]i depletion during hyperglycemic ischemia may be a more important factor in recovery than end-ischemic pHi per se. We speculate that higher [HCO3-]i may improve glial cell buffering capacity or decrease iron availability for hydroxyl radical production.
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PMID:Bicarbonate conservation during incomplete cerebral ischemia with superimposed hypercapnia. 190 5

Myo-inositol hexaphosphate (phytic acid), a highly charged antioxidant, has been found to chelate metal ions such as iron and calcium and to scavenge hydroxyl radicals, .OH. This study examined the efficacy of this antioxidant and redox agent in attenuating myocardial reperfusion injury. Sprague-Dawley rats were injected intravenously with three different doses of phytic acid (group 1, saline solution only, control; group 2, 1.5 mg/100 g; group 3, 7.5 mg/100 g; group 4, 15 mg/100 g) 30 minutes before excision of hearts. Isolated hearts were prepared by the Langendorff technique. Global ischemia was induced for 30 minutes, followed by 30 minutes of reperfusion. As expected, in group 1, reperfusion was associated with enhanced creatine kinase release, reduced coronary flow, poor recovery of ventricular function as evidenced by reduced left ventricular developed pressure and the first derivative of left ventricular pressure, and increased lipid peroxidation. Groups 3 and 4, but not group 2, demonstrated myocardial protection as evidenced by reduced creatine kinase release, improved left ventricular function and coronary flow, and decreased lipid peroxidation compared with the control group. These results suggest that potential use of this antioxidant in salvaging the heart from ischemic and reperfusion injury.
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PMID:Protection of ischemic heart from reperfusion injury by myo-inositol hexaphosphate, a natural antioxidant. 192 56

Iron-dependent oxy radicals have been implicated in reperfusion injury. Although the iron chelator desferoxamine (DFO) is beneficial, its hemodynamic effects and short vascular retention limit its use in vivo. We tested whether DFO conjugated to a high-molecular-weight starch might ameliorate in vivo hepatic microvascular injury without adverse side effects following 120 min of ischemia. Prior to reperfusion, conjugated DFO (100 mg/kg), vehicle (Veh), or saline (I/R) was administered. After 90 min of reperfusion, blood was collected for serum transaminase determination (ALT; U/liter), and fluorescein-albumin was injected to label perfused microvessels, which were quantified in frozen sections by a point-count technique. Tissue edema was estimated by wet to dry weight ratios (W/D). Reperfusion results in hepatocyte injury (rise in ALT and W/D) and a 30% loss of perfused microvessels. Intravenous administration of conjugated DFO produces no significant change in systemic hemodynamics, whereas both ALT and tissue edema were decreased by approximately 50%. Moreover, perfused microvessels were restored virtually to nonischemic control levels. Enhanced perfusion and attenuated cell injury with DFO suggest that microvascular failure and resultant cell death are mediated, at least in part, by iron-dependent mechanisms in reperfusion.
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PMID:Conjugated desferoxamine attenuates hepatic microvascular injury following ischemia/reperfusion. 193 29

Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is delocalization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of alpha-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or alpha-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.
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PMID:Acidosis-induced ischemic brain damage: are free radicals involved? 205 Jul 47


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