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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of 70 kDa heat shock protein (HSP-70) in focal ischemia occurs in regions that sustain sub-lethal ischemic injury, and may therefore be considered as a biological marker of the ischemic penumbra. In a rat embolic stroke model, using fibrin-rich emboli, we correlated the expression of HSP-70 mRNA with diffusion magnetic resonance imaging (MRI) to determine if HSP-70 mRNA expression was associated with alterations in the apparent diffusion coefficient (ADC) of brain tissue water, a putative early marker of cytotoxic injury that is readily measured in vivo. Serial ADC measurements were made for 120 min following embolic infarction in the right carotid artery territory. HSP-70 mRNA expression was observed at the boundaries of the densely ischemic zone, as judged by diffusion imaging. ADC values observed in HSP-70 mRNA-positive regions were intermediate between those observed in the ischemic core or in control regions. In addition, the volume of HSP-70 mRNA-positive tissue correlated positively with the volume of tissue showing intermediate ADC values at 120 min. These findings suggest that intermediate ADC values occur in penumbral regions. Heterogeneity of ischemic cellular injury is suggested as the basis for the intermediate ADC values observed in these regions.
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PMID:Correlation of diffusion MRI and heat shock protein in a rat embolic stroke model. 912 12

Microcirculatory impairments have theoretically been proposed as a potential factor in the development of ischemic injury, but few attempts have been made to directly assess microvascular patency following stroke. To address this issue we investigated the temporal changes in microvascular perfusion induced by permanent focal ischemia. Halothane-anesthetized spontaneously hypertensive rats were subjected to middle cerebral artery occlusion (MCAO) of 5 min to 4 h duration. Two fluorescent tracers (FITC-dextran and Evans blue) were then sequentially administered i.v. and allowed to circulate for 10 and 5 s respectively. Tissue sections were examined by fluorescent microscopy, and the mean number of perfused microvessels/mm2 calculated for cortical areas representing non-ischemic (Region A), perifocal/penumbral (Region B) and core ischemic (Region C) regions. For sham-operated controls, virtually all microvessels perfused with tracer within 5 s. In contrast MCAO induced significant reductions in the number of perfused microvessels in Regions B and C. The most marked impairments in perfusion were observed in core MCA territory (e.g. 2-10% of control values for 5 s circulation period) while, initially, the deficit was less severe in penumbral cortex. However, a secondary perfusion impairment developed over time in the perifocal/penumbral region, so that the deficit was greater 4 h after MCAO than at earlier time points (e.g. 72%, 71% and 22% of control value for 0.5, 1 and 4 h MCAO respectively; 10 s circulation period). In conclusion, MCAO induced severe impairments in microcirculatory perfusion within the core ischemic region, and to a lesser extent in the penumbra. However, the development of a more severe perfusion deficit in the penumbra within 4 h of MCAO supports the hypothesis that microcirculatory failure in this region contributes to its recruitment to the ischemic infarct.
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PMID:Temporal impairment of microcirculatory perfusion following focal cerebral ischemia in the spontaneously hypertensive rat. 913 19

We describe a novel approach for analysing the hemodynamic alterations that result after focal cerebral ischemia. This approach utilizes a temporal correlation analysis of first pass transit data obtained with functional imaging. First pass transits of injected contrast agents are measured with dynamic CT scanning. Normal transit profiles are obtained from contralateral cortical regions to serve as reference profiles. Normalized correlations are then calculated to compare transit profiles from each individual pixel within the brain to the normal reference profile. The normalized correlation coefficient is used as a measure of temporal similarity to quantitatively assess deviations from normal hemodynamics. The method is based on the premise that perturbed hemodynamics are manifested as changes in the shape of the cerebral transit profiles. Correlation maps are produced that display regional alterations in cerebral hemodynamics. Results from rabbit (n=4) and rat (n=4) models of focal ischemia are presented. In the normal contralateral hemisphere, correlation values range from 0.83-0.93 with coefficients of variation of less than 3-4% . The ischemic core is comprised of regions without significant bolus transit. The peripheral zones that lie between normal brain and the ischemic core are composed of intermediate correlation values. By setting statistical thresholds (mean minus 2SD, p < 0.05), we quantitatively define these intermediate zones as the hemodynamic penumbra, i.e. regions where the shape of the first pass transit profile has been altered. The resulting correlation maps clearly image gradients of altered cerebral hemodynamics. Perfusion indices calculated based on transit profile peaks revealed that the penumbral zones possess reduced perfusion on the order of about 40 percent of contralateral values. In summary, we believe that temporal correlation analysis of first pass transit profiles can be used to image the hemodynamic penumbra in focal cerebral ischemia.
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PMID:Hemodynamic alterations in focal cerebral ischemia: temporal correlation analysis for functional imaging. 916 70

The present experiments were undertaken to explore the mechanisms of secondary brain damage in focal ischemia of long duration (2 h), followed by recirculation. Recirculation has previously been found to cause partial recovery and secondary deterioration of cellular bioenergetic state, the subsequent damage being ameliorated by a free radical spin trap, alpha-phenyl-N-tert-butyl nitrone (PBN), even when the drug was given 1 (or 3) h after the start of recirculation. Our objective was to assess whether the secondary deterioration of the cellular bioenergetic state is due to mitochondrial dysfunction and to study whether PBN acts by preventing secondary damage to mitochondria. Focal and perifocal ("penumbral") tissues were sampled after 2 h of ischemia and after 1, 2, and 4 h of recirculation; at the latter two times, vehicle- and PBN-injected animals were studied, PBN being given after 1 h of recirculation. Homogenates were prepared, and stimulated (+ADP), nonstimulated (-ADP), and uncoupled respiratory rates were measured polarographically. The results were similar in focus and penumbra, albeit more pronounced in the focus. Ischemia was associated with a decrease in ADP-stimulated and uncoupled respiration rates, with a marked fall in the respiratory control ratio, defined as ADP-stimulated divided by nonstimulated respiration. Recirculation (1 h) brought about partial recovery, but continued reflow (2 and 4 h) was associated with a secondary deterioration of respiratory functions. This deterioration was prevented by PBN, given 1 h after the start of recirculation. The results raise the question whether the secondary deterioration of the cellular bioenergetic state in focal ischemia-reperfusion is due to secondary mitochondrial dysfunction and whether the amelioration of the subsequent damage by PBN is partly or wholly due to the effect of the spin trap on the mitochondria.
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PMID:Delayed treatment with alpha-phenyl-N-tert-butyl nitrone (PBN) attenuates secondary mitochondrial dysfunction after transient focal cerebral ischemia in the rat. 917 22

This study examined the effect of glycine recognition site antagonism (ACEA 1021) on the incidence of spontaneous depolarizations in the penumbra of a focal ischemic lesion. Rats were administered either vehicle (n = 7), ACEA 1021 (n = 7) or dizocilpine (n = 5) and then underwent 90 min middle cerebral artery occlusion. The cortical direct current (DC) potential was recorded. During ischemia, 7 +/- 3 DC shifts occurred in the vehicle group. ACEA 1021 did not reduce this frequency (7 +/- 2 DC shifts) although dizocilpine did (1 +/- 1 DC shifts; p = 0.02). The previously demonstrated neuroprotective property of ACEA 1021 during focal cerebral ischemia cannot be attributed to reduction of spontaneous depolarization in the ischemic penumbra.
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PMID:Glycine antagonism does not block ischemic spontaneous depolarization in the rat. 917 1

The effect of the novel inhibitor of receptor-activated and calcium store-operated nonselective cation channels, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-gamma 1)-2-phenyl-N, N-di-[2(2,3,4-trimethoxyphenyl) ethyl]acetamide (LOE 908 MS), on focal cerebral ischemia was studied in halothane-anesthetized rats submitted to permanent suture occlusion of the right middle cerebral artery (MCA). The treated group (n = 7) received subcutaneous injections of 30 mg/kg LOE 908 MS (in 1 ml saline) 10 min after vascular occlusion and again after 3 h. The untreated group (n = 11) was injected subcutaneously with 1 ml saline at the same times. Evolution of infarct was monitored by electrophysiological recording of EEG and cortical steady potential and by diffusion-weighted magnetic resonance imaging during the initial 6 h of vascular occlusion. The hemodynamic, biochemical, and morphological changes were studied after 6 h by combining autoradiographic measurement of blood flow with histological stainings and pictorial measurements of ATP, glucose, and tissue pH. In the untreated animals, the ischemic lesion volume [defined as the region in which the apparent diffusion coefficient (ADC) of water declined to below 80% of control] steadily increased by approximately 50% during the initial 6 h of vascular occlusion relative to the first set of data 10 min postocclusion. In the treated animals, in contrast, the ADC lesion volume declined by approximately 20% during the same interval. Treatment also led to a significant reduction in the number of periinfarct depolarizations. After 6 h of vascular occlusion, blood flow was significantly higher in the treated animals, and the volume of ATP-depleted and morphologically injured tissue representing the infarct core was 60-70% smaller. The volume of severely acidic tissue, in contrast, did not differ, indicating that LOE 908 MS does not reduce the size of ischemic penumbra. These findings demonstrate that postocclusion treatment of permanent focal ischemia with LOE 908 MS delays the expansion of the infarct core into the penumbra for a duration of at least 6 h and therefore substantially prolongs the window of opportunity for the reversal of the ischemic impact in the peripheral parts of the evolving infarct.
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PMID:Inhibition of nonselective cation channels reduces focal ischemic injury of rat brain. 918 91

We review the molecular and biochemical events that occur within the brain during cerebral ischemia, based on recent investigations of focal cerebral ischemia models. Occlusion of the middle cerebral artery in rats produces focal ischemia. In contrast to the core where ischemia is severe and infarction develops rapidly, areas surrounding the core (called the penumbra) show a more moderate decrease of blood flow and can tolerate longer durations of ischemic stress. Reperfusion and pharmacological interventions can help to salvage the penumbra. Ischemic insult alters the genomic properties of the brain cells and selective production of heat shock proteins can be seen. Heat shock proteins are necessary in the repair of cell integrity, and is thought to be induced as a rescue program. Pre-ischemic induction of these proteins is known to cause ischemic tolerance, and methods to manipulate genes into inducing HSPs may be effective in protecting neurons from ischemia. Genes that promote apoptosis are also expressed after ischemia, and may cause secondary expansion of the infarction. Strategies to denote expression of these genes may be effective in reducing ischemic neuronal death. Activation of the inflammatory cells such as neutrophils and macrophages, in the ischemic region, may cause further post-ischemic damage. Investigations on the role and mechanics of inflammatory systems in ischemic neuronal injury may present a new target for therapeutic intervention against stroke.
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PMID:Molecular and biochemical events within the brain subjected to cerebral ischemia (targets for therapeutical intervention). 918 39

Using in situ DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL), we investigated the evolution of DNA strand breaks, a marker of DNA damage, in rat brain after 1 h of middle cerebral artery occlusion and various durations of reperfusion. DNA single-strand breaks (SSBs) detected by PANT were present in neurons after as little as 1 min of reperfusion. Numbers of neurons containing an SSB increased progressively in the ischemic core but decreased in the ischemic penumbra after 1 h of reperfusion. DNA double-strand breaks (DSBs) detected by TUNEL were first seen in neurons after 1 h of reperfusion, and their numbers then increased progressively in the ischemic core, with a regional distribution similar to that of SSBs. However, the number of SSB-containing cells was greater than that of DSB-containing cells at all time points tested. SSB-containing cells detected within the first hour of reperfusion were exclusively neuronal and exhibited normal nuclear morphology. At 16-72 h of reperfusion, many SSB- and DSB-containing cells, including both neurons and astrocytes, showed morphological changes consistent with apoptosis. Gel electrophoresis of DNA isolated from the ischemic core showed DNA fragmentation at 24 h, when both SSBs and DSBs were present, but not at 1 h, when few DSBs were detected. These results suggest that damage to nuclear DNA is an early event after neuronal ischemia and that the accumulation of unrepaired DNA SSBs may contribute to delayed ischemic neuronal death, perhaps by triggering apoptosis.
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PMID:Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. 920 15

Cerebral ischemia and also excitotoxicity induce the expression of 72,000 mol. wt heat shock protein (Hsp70), c-Fos, and cyclooxygenase-2. In the present work we have examined whether Hsp70, c-Fos and cyclooxygenase-2 are expressed by the same cells in the rat brain at 6, 12 and 24 h following transient focal ischemia or kainic acid administration, by means of single and double immunohistochemistry. At 6 h after kainic acid, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen in pyramidal hippocampal neurons and superficial cortical layers, however by 24 h such colocalization became rare within the cortex but was partially maintained in the hippocampus. Cyclooxygenase-2 was seen in many neurons that were also immunoreactive for c-Fos in superficial cortical layers, dentate gyrus and pyramidal cell layer of the hippocampus from 6 h after kainic acid. Co-localization of cyclooxygenase-2 and c-Fos was also observed in superficial cortical layers within the ipsilateral hemisphere at 6 h following focal ischemia. Also, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen at this time. However, by 24 h cyclooxygenase-2 and c-Fos-immunoreactive cells were restricted to perifocal regions, and only a very limited co-localization with Hsp70 was seen in perifocal neurons located in the border of the penumbra-like area that surrounds the ischemic core and is strongly immunoreactive for Hsp70. This study shows a selective and dynamic cellular expression of inducible proteins following either ischemia or kainic acid, with a remarkable neuronal co-localization of c-Fos and cyclooxygenase-2. The results suggest that, first, stimuli underlying neuronal c-Fos expression can also lead to the induction of cyclooxygenase-2; second, transient co-localization of Hsp70 and c-Fos can take place in non-vulnerable neurons; and finally, expression of c-Fos, cyclooxygenase-2, and/or Hsp70 at a given time-point is part of the response to altered environmental conditions and can be related to the particular cellular sensitivity rather than the pathological outcome.
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PMID:Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid. 925 33

Endothelin-1 (ET-1) was unilaterally applied onto the surface of the dorsal frontoparietal cortex of the rat. Cortical blood flow measurements using laser-Doppler flowmetry demonstrated dose-dependent reductions of frontoparietal cortical blood flow. Histological analysis demonstrated dose-related lesions and the time course was followed using MRI. The lesions appear to be associated with a large penumbra area indicated by morphological characteristics. Thus, cortical surface exposure to ET-1 may produce graded lesions of the frontoparietal cortex related to local ischemia.
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PMID:Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia. 926 39


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