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)

A carotid embolic stroke model in rats was studied with a combination of diffusion- and perfusion-sensitive magnetic resonance (MR) imaging at 4.7 T. Capillary blood deoxygenation changes were monitored during formation of focal ischemia by acquiring multisection magnetic susceptibility-weighted echo-planar images. A signal intensity decrease of 7% +/- 3 in ischemic brain (1% +/- 2 in normal brain) was attributable to a T2* decrease due to increased blood deoxygenation, which correlated well with subsequently measured decreases in the apparent diffusion coefficient. The same multisection methods were used to track the first-pass transit of a bolus of dysprosium-DTPA-BMA [diethylenetriaminepentaacetic acid-bis(methylamide)] to assess relative tissue perfusion before and after stroke and after treatment with a thrombolytic agent. Analysis of contrast agent transit profiles suggested a total perfusion deficit in ischemic tissue and essentially unchanged perfusion in normal brain tissue after stroke.
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PMID:Perfusion and diffusion MR imaging of thromboembolic stroke. 840 May 61

Polyamines and N-methyl-D-aspartate (NMDA) receptors are both thought to play an important role in secondary neuronal injury after cerebral ischemia. Ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, was studied after transient focal cerebral ischemia occurred. Spontaneously hypertensive male rats, each weighing between 250 and 350 g, underwent 3 hours of tandem middle cerebral artery (MCA) and common carotid artery occlusion followed by reperfusion for a period of 3 hours or 21 hours. Intravenous ifenprodil (10 microg/kg/minute) or saline infusion was started immediately after the onset of MCA occlusion and continued throughout the ischemic period. Physiological parameters including blood pressure, blood gas levels, blood glucose, hemoglobin, and rectal and temporal muscle temperatures were monitored. Six rats from each group were evaluated at 6 hours postocclusion for brain water content, an indicator of brain edema, and Evans blue dye extravasation for blood-brain barrier breakdown. Infarct volume was also measured in six rats from each group at 6 and 24 hours postocclusion. Ifenprodil treatment significantly reduced brain edema (82.5 +/- 0.4% vs. 83.5 +/- 0.4%, p < 0.05) and infarct volume (132 +/- 14 mm3 vs. 168 +/- 25 mm3, p < 0.05) compared with saline treatment, with no alterations in temporal muscle (brain) or rectal (body) temperature (35.9 +/- 0.4 degrees C vs. 36.2 +/- 0.2 degrees C; 37.7 +/- 0.4 degrees C vs. 37.6 +/- 0.6 degrees C; not significant). These results demonstrate that ifenprodil has neuroprotective properties after ischemia/reperfusion injury in the absence of hypothermia. This indicates that antagonists selective for the polyamine site of the NMDA receptors may be a viable treatment option and helps to explain some of the pathophysiological mechanisms involved in secondary injury after transient focal cerebral ischemia has occurred.
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PMID:Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia. 938 5

Although freshwater turtles as a group are highly anoxia tolerant, dramatic interspecific differences in the degree of anoxia tolerance have been demonstrated in vivo. Painted turtles (Chrysemys picta bellii) appear to be the most hypoxia-tolerant species thus far studied, while softshelled turtles (Trionyx spinifer) are the most hypoxia-sensitive. We have assumed that this dichotomy persists in vitro but have not, until now, directly tested this assumption. We therefore, directly compared the responses of isolated, perfused, working hearts from these two species to either 240 min of anoxia, 90 min of global ischemia, or 240 min of global ischemia followed by reoxygenation/reperfusion. Isolated hearts were perfused at 20 degrees C and monitored continuously for phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi), and intracellular pH (pHi) by 31P-nuclear magnetic resonance spectroscopy as well as for ventricular developed pressure and heart rate. Contrary to our expectations, we observed few significant differences in any of these parameters between painted and softshelled turtle hearts. Hearts from both species tolerated 240 min of anoxia equally well and both restored PCr, pHi, and Pi contents to control levels during reoxygenation. We did observe some significant interspecific differences in the 90 min (pHi and Pi) and 240 min (PCr) ischemia protocols although these seemed to suggest that Trionyx hearts might be more tolerant to these stresses than Chrysemys hearts. We conclude that: (a) the observed in vivo differences in anoxia tolerance between painted and softshelled turtles must either be due to differences in organ metabolism in organs other than the heart (e.g., brain) or to some integrative physiologic differences between the species; and (b) isolated hearts from a species known to be relatively anoxia sensitive in vivo can exhibit an apparent high degree of anoxia and ischemia tolerance in vitro.
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PMID:In vitro tolerance to anoxia and ischemia in isolated hearts from hypoxia sensitive and hypoxia tolerant turtles. 950 38

Previous studies have shown that administration of the N-methyl-d-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-phosphonic acid (CPP) reduces NMDA-mediated neurotoxicity in animal models of hypoxia/ischemia but also may induce brain tissue vacuolization and alter glucose metabolism. The present study tests the hypothesis that CPP administration alters brain cell membrane structure and function in the cerebral cortex of normoxic newborn piglets through the generation of oxygen free radicals and induction of lipid peroxidation. Twenty six anesthetized, ventilated newborn piglets-13 treated with 2 mg/kg i.v. CPP and 13 untreated controls-were studied. ATP and phosphocreatine (PCr) levels were measured as an index of cellular energy metabolism and tissue glucose levels determined. Na+, K+-ATPase activity was measured as an index of brain cell membrane function and the lipid peroxidation products conjugated dienes (CD) and fluorescent compounds (FC) measured. Free radical generation was detected on cortical biopsies homogenized with alpha-phenyl-N-tert-butyl-nitrone (PBN) through electron spin resonance spectroscopy. Signal height of spectrum was divided by dry tissue weight and expressed as mm/g tissue. In the two groups brain tissue ATP and PCr levels were not different. Tissue glucose levels were higher in the CPP group (24+/-5 mg/dl) than in controls (14+/-3 mg/dl), p<0.05, whereas Na+,K+-ATPase activity was lower in the CPP group than in controls (34+/-4 vs. 43+/-6 micromol Pi/mg protein/h), p<0.05. Lipid peroxidation products were higher in the CPP group (CD: 57+/-19 nmol/g brain, FC: 1.5+/-0.3 microg/g brain) than in controls (CD: 0+/-0 nmol/g brain, FC: 0.9+/-0.2 microg/g brain), p<0. 05. Free radical intensity was higher in the CPP group (493+/-397 mm/g tissue) than in controls (51+/-83 mm/g tissue), p<0.05. In vitro administration of CPP to brain cell membranes did not change Na+,K+-ATPase activity or the generation of lipid peroxidation products. The data demonstrate that administration of CPP induces lipid peroxidation, results in free radical generation, decreases brain cell membrane Na+,K+-ATPase activity and alters glucose metabolism in the cerebral cortex of newborn piglets. Since CPP is a potent antagonist of the NMDA receptor, we speculate that CPP generates free radicals through a pathway independent of the NMDA receptor by altering cellular metabolism and possibly glucose utilization during normoxia in newborn piglets.
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PMID:Deleterious brain cell membrane effects after NMDA receptor antagonist administration to newborn piglets. 987 67

Much confusion has arisen recently over the question of whether excitotoxic neuronal degeneration can be considered an apoptotic phenomenon. Here, we addressed this question by using ultrastructural methods and DNA fragmentation analysis to compare a prototypic apoptotic in vivo central nervous system cell death process (physiologic cell death in the developing rat brain) with several central nervous system cell death processes in the in vivo infant rat brain that are generally considered excitotoxic (degeneration of hypothalamic neurons after subcutaneous administration of glutamate and acute neurodegeneration induced by hypoxia/ischemia or by concussive head trauma). We found by ultrastructural analysis that glutamate induces neurodegenerative changes in the hypothalamus that are identical to acute changes induced in the infant rat brain by either hypoxia/ischemia or head trauma, and that these changes are fundamentally different both in type and sequence from those associated with physiologic cell death (apoptosis). In addition, we show by ultrastructural analysis that concussive head trauma induces both excitotoxic and apoptotic neurodegeneration, the excitotoxic degeneration being very acute and localized to the impact site, and the apoptotic degeneration being delayed and occurring in regions distant from the impact site. Thus, in the head trauma model, excitotoxic and apoptotic degeneration can be distinguished not only by ultrastructural criteria but by their temporal and spatial patterns of expression. Whereas ultrastructural analysis provided an unambiguous means of distinguishing between excitotoxic and apoptotic neurodegeneration in each example analysed in this study, DNA fragmentation analysis (TUNEL staining or gel electrophoresis) was of no value because these tests were positive for both processes.
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PMID:Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain. 1034 Apr 98

Mexiletine is a class I antiarrhythmic drug with neuroprotective effects in models of brain ischemia attributable to inhibition of brain sodium channels. We compared effects of R-mexiletine on wild-type and mutant rat brain (rbIIA) and heart (rh1) sodium channel alpha-subunits transiently expressed in tsA-201 cells. R-mexiletine induced tonic and frequency-dependent block and bound with a 26-fold (brain) or 35-fold (heart) higher affinity to inactivated sodium channels. Affinities of both resting and inactivated channels for R-mexiletine block were approximately 2-fold higher for heart than for brain channels. Mutations in transmembrane segment IVS6 of heart (rhF1762A) and brain (rbF1764A and rbY1771A) channels, which reduce block by other local anesthetics, reduced high-affinity block of inactivated channels and frequency-dependent block of open channels by R-mexiletine and abolished the difference in affinity between brain and heart sodium channels. Unlike previous local anesthetics studied, the strongest effect was observed for mutation rbY1771A. Comparison of mutations of the homologous phenylalanine residue in brain and heart channels showed striking differences in the effects of the mutations. rbF1764A reduced drug block by slowing R-mexiletine binding to inactivated channels, whereas rhF1762A reduced block by increasing the rate of dissociation from inactivated and resting channels. Thus, rbF1764/rhF1762 is a critical determinant of affinity and tissue-specific differences in mexiletine block of brain and heart sodium channels, but its role in drug interaction differs in these two channel isoforms.
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PMID:Differential interaction of R-mexiletine with the local anesthetic receptor site on brain and heart sodium channel alpha-subunits. 1057 51

Freshly sampled brain tissue exposed to 2,3,5-triphenyltetrazolium chloride (TTC) acquires a red color because mitochondrial enzymes reduce the colorless TTC to a red, water-insoluble formazan deposit. Pan-necrotic areas remain uncolored, which enables quantitation of experimental brain injury by optical scanning and image analysis of serial slices to determine the relative volume of red versus infarcted, non-stained, tissue. The accuracy of this method can be challenged, however, when infarction is accompanied by areas of partial, scattered injury where differences in coloration are difficult to see or quantify. We tested the feasibility of measuring scattered injury using a principle which underlies standard assays for in vitro cell survival, namely extracting deposited formazan with a solvent and measuring its level by spectrophotometry. Anesthetized, adult Sprague Dawley rats were subjected to 12 min of cerebral ischemia to produce selective, delayed neuronal death in hippocampus, striatum and cortex. Some rats also received 6 h of whole-body hypothermia treatment (31.5-32.5 degrees C) immediately after ischemia. Ischemia rats and non-operated controls were sacrificed 1 week later. Hippocampus and portions of cerebrum were incubated 90 min in a 2% TTC solution and then soaked in a measured volume of 50:50 ethanol and dimethylsulfoxide to extract the red formazan product. Spectrophotometric measurements of the extract showed a diminished formazan coloration (absorbance/g brain) in all samples from the untreated ischemia group compared to non-operated controls. This apparent brain injury was attenuated in the group of ischemia rats that received hypothermia treatment. We conclude that solvent extraction and spectrophotometric quantitation of formazan has potential utility as an objective way to index experimental brain injury even if this is diffuse in nature and not amenable to measurement by conventional image analysis techniques.
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PMID:Spectrophotometric measurement of experimental brain injury. 1066 38

OBJECTIVE: Life-threatening conditions cause severe changes in the organization and conformation of macromolecules, creating urgent requirements for protein repair to ensure survival. As molecular chaperones, heat shock proteins (HSP) that have specialized functions in protein folding are now well established to restore homeostasis in cells and organisms. Augmentation of HSP synthesis is tightly regulated by stress-inducible heat shock factors (HSF), which are part of a transcriptional signaling cascade with both positive (e.g., HSP) and negative (e.g., proinflammatory cytokines) properties. In this review, we discuss the biological roles and mechanisms of HSP-mediated protection in pathophysiologic conditions (ischemia, sepsis, and preeclampsia) and the regulation for stress-dependent HSP synthesis and speculate about future applications for harnessing HSF and HSP partners as cytoprotective agents. DATA SOURCES: Reactive oxygen species are major pathogenic factors in cell death pathways (e.g., necrosis, apoptosis), in part, because of proteotoxic effects. In intact organisms, forced overexpression of HSP per se affords effective counterbalance against ischemia challenges (e.g., heart and brain) and systemic conditions (e.g., sepsis). Besides stressful conditions, gene-targeting studies have uncovered new functions for heat shock transcription factors (e.g., maintenance of intrauterine pregnancy) in mammals. In parallel, pharmacologic studies using small molecules are paving the way for future prospects to exploit the beneficial properties of HSP, albeit an important but presently elusive goal. CONCLUSIONS: Together, HSF and HSP partners are attractive targets in therapeutic strategies designed to stimulate endogenous protective mechanisms against deleterious consequences of oxidative stress. With further technological advances, it is anticipated that the spotlight on HSP, alone or in combination with other stress response pathways, could, ultimately, reduce injury and accelerate functional recovery of susceptible organs in living organisms including humans.
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PMID:Heat shock factor 1 and heat shock proteins: Critical partners in protection against acute cell injury. 1183 44

The balance between oxygen consumption and delivery in the rat brain after exposure to transient ischemia was quantitatively studied with single-spin echo T2-BOLD (blood oxygenation level-dependent) magnetic resonance imaging at 4.7 T. The rats were exposed to graded common carotid artery occlusions using a modification of the four-vessel model of Pulsinelli. T2, diffusion, and cerebral blood volume were quantified with magnetic resonance imaging, and CBF was measured with the hydrogen clearance method. A transient common carotid artery occlusion below the CBF value of approximately 20 mL x 100 g(-1) x min(-1) was needed to yield a T2 increase of 4.6 +/- 1.2 milliseconds (approximately 9% of cerebral T2) and 6.8 +/- 1.7 milliseconds (approximately 13% of cerebral T2) after 7 and 15 minutes of ischemia, respectively. Increases in CBF of 103 +/- 75% and in cerebral blood volume of 29 +/- 20% were detected in the reperfusion phase. These hemodynamic changes alone could account for only approximately one third of the T2 increase in luxury perfusion, suggesting that a substantial increase in blood oxygen saturation (resulting from reduced oxygen extraction by the brain) is needed to explain the magnetic resonance imaging observation.
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PMID:Quantitative assessment of the balance between oxygen delivery and consumption in the rat brain after transient ischemia with T2 -BOLD magnetic resonance imaging. 1189 31

Whereas several studies have addressed the activation of microglia (the resident mononuclear phagocytes of the brain) and macrophages within the nervous system in experimental animal models of congenital and induced hydrocephalus, little is known of their state of activation or regional distribution in human fetal hydrocephalus. This investigation aimed to address such questions. Ten human fetal cases [20-36 gestational weeks (GW) at postmortem] previously diagnosed with hydrocephalus on ultrasound examination in utero, and 10 non-hydrocephalic controls (22-38 GW at postmortem) were assessed immufcnohistochemically with antibodies directed against MHC class II and CD68 antigens, and lectin histochemistry with Lycopersicon esculentum (tomato lectin). Adjacent sections were also immunoreacted with an antiserum to laminin to detect cerebral blood vessels. Eight out of the 10 hydrocephalus cases showed numerous CD68 and tomato lectin-positive macrophages located at focal regions along the ependymal lining of the lateral ventricles (particularly within the occipital horn). However, only five of these cases demonstrated MHC class II positive macrophages associated with the ventricular lining. Microglial reactivity within periventricular regions could also be identified using the lectin in four cases, two of which were also immunoreactive with CD68 (but not with MHC class II). By comparison, in control cases five out of 10 fetal brains (aged between 20 and 24 GW) showed few or no ependymal or supraependymal macrophages. One case at 28 GW, and cases at 32 and 38 GW (two of which were diagnosed with intrauterine hypoxic-ischemia) did, however, show some MHC class II (CD68 negative) cells located at the ependymal surface. Nevertheless, these were not as numerous or intensely immunoreactive as in the hydrocephalus cases. Microglia interspersed throughout the intermediate zone and circumscribing the basal ganglia were within normal confines in all cases examined. Hydrocephalic cases additionally showed focal regions of hypovascularization or alterations in the structure and orientation of capillaries within periventricular areas, compared to controls. The macrophage response detected at the ependymal lining of the ventricles and within the periventricular area in hydrocephalus may be related both to the severity of hydrocephalus and the age of the fetus.
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PMID:Brain macrophages and microglia in human fetal hydrocephalus. 1516 71


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