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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue damage in cerebral ischemia may be produced by acidosis-induced delocalization of intracellular iron which acts as a catalyst in oxidative reactions. Acidosis was induced either by homogenization and incubation of rat cortical homogenates in acidified buffers or by submitting hyperglycemic rats to complete ischemia, a procedure that leads to intracellular lactic acidosis. The level of low molecular weight species (LMWS) iron was measured after filtration of tissue homogenates through a 10,000 Mr ultrafiltration membrane. When cortical tissue was homogenized in buffer pH 7, the level of LMWS iron was equal to 0.21 microgram/g. It was significantly enhanced by acidification of the homogenization medium, reaching 0.34 microgram/g at pH 6 and 0.75 microgram/g at pH 5. When the tissue was homogenized in water, the LMWS iron level reached 0.17 microgram/g in normoglycemic rats and 0.38 microgram/g (p < .05) in hyperglycemic rats. Both aerobic incubation of homogenates for 1 h at 37 degrees C and inclusion of EDTA in the homogenization medium led to further increases in the iron level. In order to demonstrate the deleterious role of iron in brain ischemia, the effect of treatment with bipyridyl, an iron-chelating agent, was assessed by measuring regional brain edema by the specific gravity method, 24 h following induction of thrombotic brain infarction. The treatment significantly attenuated the development of brain edema, reducing the water content of the infarcted area by about 2.5%. Taken together, these results support the hypothesis that a significant component of brain ischemic injury involves an iron-dependent mechanism.
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PMID:Ischemia-induced brain iron delocalization: effect of iron chelators. 807 Jun 93

An imaging technique capable of detecting ischaemic cerebral injury at an early stage could improve diagnosis in acute or transient cerebral ischaemia. We compared the ability of superparamagnetically contrast-enhanced MRI and conventional T2-weighted MRI to detect ischaemic injury early after unilateral occlusion of the middle cerebral artery in 12 male Wistar rats. Permanent vessel occlusion was achieved by a transvascular approach, which has the advantage of not requiring a craniectomy. At 45-60 min after the procedure, the animals had conventional T2-weighted MRI before and after administration of a superparamagnetic contrast agent (iron oxide particles). Unenhanced images were normal in all animals. After administration of iron oxide particles, the presumed ischaemic area was clearly visible, as relatively increased signal, in all animals; this high signal area corresponded to the area of ischaemic brain infarction seen on histological studies. Magnetic susceptibility effects of iron particles cause low signal in normally perfused cerebral tissue, whereas tissue with reduced or absent blood flow continues to give relatively high signal. Our results suggest that superparamagnetic iron particles may significantly reduce the interval between an ischaemic insult and the appearance of parenchymal changes on MRI.
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PMID:MRI in acute cerebral ischaemia: perfusion imaging with superparamagnetic iron oxide in a rat model. 810 90

Oxygen free radicals have been implicated as a causal factor in posttraumatic neuronal cell loss following cerebral ischemia and head injury. The conversion of salicylate to dihydroxybenzoic acid (DHBA) in vivo was employed to study the formation of hydroxyl radical (.OH) following central nervous system (CNS) injury. Bilateral carotid occlusion (BCO) in gerbils and concussive head trauma in mice were selected as models of brain injury. The lipid peroxidation inhibitor, tirilazad mesylate (U-74006F), was tested for its ability to attenuate hydroxyl radical formation in these models. In addition, U-74006F was studied as a scavenger of hydroxyl radical in an in vitro assay based on the Fenton reaction. For in vivo experimentation, hydroxyl radical formation was expressed as the ratio of DHBA to salicylate (DHBA/SAL) measured in brain. In the BCO model, hydroxyl radical formation increased in whole brain with 10 min of occlusion followed by 1 min of reperfusion. DHBA/SAL was also found to increase in the mouse head injury model at 1 h postinjury. In both models, U-74006F (1 or 10 mg/kg) blocked the increase in DHBA/SAL following injury. In vitro, reaction of U-74006F with hydroxyl radical gave a product with a mol wt that was 16 greater than U-74006F, indicative of hydroxyl radical scavenging. We speculate that U-74006F may function by blocking oxyradical-dependent cell damage, and thereby maintaining free iron (which catalyzes hydroxyl radical formation) concentrations at normal levels.
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PMID:The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury. Reversal by tirilazad mesylate (U-74006F). 829 19

In cerebral ischemia of different degrees, the amplitudes of somatosensory evoked potentials (SEPs) are facilitated or depressed. Different mechanisms might be responsible for the explanation of the contradictory phenomena. SEPs obtained using the paired stimulation method were employed in trying to find out the role of the functional changes of the inhibitory system in the brain during ischemia. Eight rabbits were used for recording the amplitude recovery curve of paired SEPs in the normal state, and the other ten were used for recording the recovery curve in different cerebral ischemic degrees. Cerebral ischemia was induced by the iron particle injection method. The attenuation of the depressed recovery function of the paired SEP amplitudes was detected during cerebral ischemia when SEP amplitudes were either facilitated or depressed. The results indicate that the function of the inhibitory system in the brain is selectively vulnerable during cerebral ischemia.
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PMID:The recovery function of paired somatosensory evoked potentials in cerebral ischemic rabbits. 856 87

Analyzing the distribution pattern of transferrin (Tf) and ferritin, we investigated the changes in iron metabolism related proteins in the process of neuronal death induced by 5 min ischemia. In the control animals, Tf immunoreactivity was localized in the oligodendrocytes. Ferritin was distributed in both neurons and gliacytes, particularly microglia. In parallel with the delayed neuronal death, Tf-positive atrophied neurons and numerous ferritin-positive gliacytes appeared in the CA1 subfield of the hippocampus 4 days after ischemia, when glia fibrillary acidic protein (GFAP)-positive astrocytes also appeared throughout the hippocampal structure. A considerable number of ferritin-positive phagocytes (reactive microglia) appeared in the stratum pyramidale from the seventh day. Our data show clearly that the mobilization of Tf and ferritin-positive phagocytes are linked with the degeneration of neurons induced by cerebral ischemia. These events may suggest an activation of iron handling system under the postischemic condition.
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PMID:Activation of iron handling system within the gerbil hippocampus after cerebral ischemia. 883 41

A novel group of compounds, the 21-aminosteroids ("lazaroids"), have been designed that are potent inhibitors of oxygen free radical-induced, iron-catalyzed lipid peroxidation (LP) in microvascular and nervous tissue. One of these, tirilazad mesylate (U-74006F), has been selected for clinical evaluation as a cerebroprotective agent. In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including: increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP-induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the levels of endogenous vitamin E. The major site of action appears to be the blood-brain barrier based upon its known localization in cerebrovascular endothelium and numerous studies showing an attenuation of subarachnoid hemorrhage (SAH), injury, and ischemia-induced blood-brain barrier permeability. Tirilazad has demonstrated neuroprotective efficacy in multiple preclinical models of spinal cord and head injury, SAH, and focal cerebral ischemia, as measured by a decrease in cerebral vasospasm, blood-brain barrier compromise, post-traumatic ischemia, edema, ischemic neuronal necrosis and infarction, and improved neurological recovery. This efficacy is correlated with a reduction in markers of oxygen radical-induced LP. Phase III clinical trials are currently ongoing in spinal cord and head injury, SAH, and ischemic stroke. Initial results from a European/Australian/New Zealand trial in SAH have shown a significant decrease in mortality and an increase in the incidence of good recovery.
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PMID:Inhibition of lipid peroxidation in central nervous system trauma and ischemia. 884 48

The aim of the study was to compare the first-passage profiles of dysprosium diethylenetriamine penta-acetic acid bis(methylamide) (DTPA BMA) and the superparamagnetic iron oxide particles NSR 0430 in regions with severe and moderate cerebral ischemia. In seven rats subjected to middle cerebral artery occlusion, two dynamic MR perfusion imaging series were acquired after intravenous bolus injections of .5 mmol/kg dysprosium DTPA BMA and .06 mmolFe/kg iron oxide particles, respectively. The doses were chosen to obtain similar maximum signal change in normally perfused brain. The first-passage profiles were compared in a region of interest (ROI) in the core area with severe ischemia and in a ROI in the penumbra area of moderate ischemia. The results were compared both as the calculated mean signal intensity versus time curves for all seven rats and statistically for an estimated mean transit time (MTT) after gamma variate fitting of the calculated concentration versus time curves. The first-passage profiles for the two contrast agents were similar, both in the core area of severe ischemia and in the penumbra area of moderate ischemia. In this rat stroke model, dysprosium DTPA BMA and the superparamagnetic iron oxide particles NSR 0430 were found to be equally efficacious for the diagnosis of the perfusion deficit, but if safe for human investigations, iron oxide particles would have an advantage as equal susceptibility effect may be achieved with smaller injection volumes.
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PMID:Comparison of dysprosium DTPA BMA and superparamagnetic iron oxide particles as susceptibility contrast agents for perfusion imaging of regional cerebral ischemia in the rat. 889 8

The effects of right carotid artery ligation on the subsequent cerebral ischemia, induced by iron particle injection, in rabbits, were evaluated by recording somatosensory evoked potentials (SEPs) and cerebral blood flow (CBF) using laser Doppler flowmetry. Iron particle injection decreased CBF over 120 min and delayed SEP onset latency in rabbits with no previous carotid artery ligation (control group). In rabbits with a carotid ligation 3 days before, iron particle injection induced the decrease of CBF, as in the control group, but did not prolong the latency of SEP. Injection of iron particles induced only a transient decrease of CBF (less than 10 min) followed by an abrupt recovery, and no prolongation of SEP latency was observed in rabbits with a carotid ligation 6 days before. These results suggest that carotid artery ligation induces a beneficial effect on cerebral function during the subsequent ischemia, which is independent on the CBF changes.
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PMID:Ligation of lateral carotid artery attenuates disturbance of brain function caused by subsequent cerebral ischemia in rabbits. 894 42

Increasing evidence indicates that glucocorticoids (GCs), produced in response to physical/emotional stressors, can exacerbate brain damage resulting from cerebral ischemia and severe seizure activity. However, much of the supporting evidence has come from studies employing nonphysiological paradigms in which adrenalectomized rats were compared with those exposed to constant GC concentrations in the upper physiological range. Cerebral ischemia and seizures can induce considerable GC secretion. We now present data from experiments using metyrapone (an 11-beta-hydroxylase inhibitor of GC production), which demonstrate that the GC stress-response worsens subsequent brain damage induced by ischemia and seizures in rats. Three different paradigms of brain injury were employed: middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia; four-vessel occlusion (4VO) model of transient global forebrain ischemia; and kainic acid (KA)-induced (seizure-mediated) excitotoxic damage to hippocampal CA3 and CA1 neurons. Metyrapone (200 mg/kg body wt) was administered systemically in a single i.p. bolus 30 min prior to each insult. In the MCAO model, metyrapone treatment significantly reduced infarct volume and also preserved cells within the infarct. In the 4VO model, neuronal loss in region CA1 of the hippocampus was significantly reduced in rats administered metyrapone. Seizure-induced damage to hippocampal pyramidal neurons (assessed by cell counts and immunochemical analyses of cytoskeletal alterations) was significantly reduced in rats administered metyrapone. Measurement of plasma levels of corticosterone (the species-typical GC of rats) after each insult showed that metyrapone significantly suppressed the injury-induced rise in levels of circulating corticosterone. These findings indicate that endogenous corticosterone contributes to the basal level of brain injury resulting from cerebral ischemia and excitotoxic seizure activity and suggest that drugs that suppress glucocorticoid production may be effective in reducing brain damage in stroke and epilepsy patients.
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PMID:Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures. 896 97

A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56-70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.
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PMID:Pyrrolopyrimidines: novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models. 915 99


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