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

Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of these data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is hypoxia due to peri-infarct spreading depression-like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri-infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non-NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region.
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PMID:Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. 791 80

Glutamate-mediated spreading depression is currently thought to be a key event in the pathogenesis of potential neuronal degeneration in the ischemic 'penumbra'. Glutamate receptor stimulation causes induction of transcription factors that belong to the class of immediate early genes (IEGs), thought to be involved in coupling neuronal excitation to target gene expression. Focal cerebral ischemia elicits a homogeneous expression of several IEGs, prominently in cortex. In the ischemic core, discrepancies are observed between mRNA and protein levels, due to a severe, persistent protein synthesis deficit, preventing the translation of IEG encoded mRNAs. Outside the ischemic core, widespread IEG expression occurs in the entire ipsilateral cortex at mRNA as well as at protein level. This homogeneous expression of transcription factors can be pinpointed to at least two different pathogenetic mechanisms by means of appropriate pharmacological antagonists. Prolonged IEG induction in the 'penumbra', an area in which neurons are metabolically compromised but not yet energy-depleted, cannot be suppressed by the administration of N-methyl-D-aspartate (NMDA) receptor antagonists. In contrast, short-lasting IEG induction in undamaged neurons remote from the ischemic territory, though also caused by ischemia-elicited spreading depression, can be blocked by NMDA receptor antagonists. In both areas, IEG expression identifies neurons destined to survive but is likely to be mediated by different signal transduction pathways, at the receptor, second messenger and/or the DNA level.
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PMID:Stimulus-transcription coupling in focal cerebral ischemia. 791 81

Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.
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PMID:Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats. 792 54

The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought to suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolarization (< 0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.
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PMID:Viability thresholds and the penumbra of focal ischemia. 794 86

Using microdialysis, we investigated the effect of hyperthermia on glutamate release in penumbral cortex of rats with 2 h of either normothermic (37 degrees C) or hyperthermic (39 degrees C) middle cerebral artery (MCA) occlusion. Penumbral blood flow (CBF) was measured by laser-Doppler flowmetry. CBF values (expressed as % preischemic values) in normothermic and hyperthermic groups were 24 +/- 11 (SD) and 24 +/- 16%, respectively, during ischemia and 102 +/- 81 and 147 +/- 79% during recirculation. Average extracellular glutamate in the hyperthermic group increased from a baseline of 7 +/- 2 microM to a peak of 217 +/- 184 microM at 10-20 min after onset of ischemia but returned to near baseline after 60 min. Glutamate in the normothermic group increased from 4 +/- 2 microM to a peak of 26 +/- 17 microM at 10-20 min after MCA occlusion but fell to near-baseline before recirculation. Thus reuptake systems appeared to remain functional in ischemic penumbra, even during hyperthermia. Ischemic glutamate release was significantly higher in hyperthermic than in normothermic rats: average values of individual rats' peak levels were 251 +/- 221 microM and 37 +/- 34 microM, respectively. The ischemic CBF threshold value for glutamate release was 33% of control in the normothermic group but 61% in the hyperthermic group.
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PMID:Effect of hyperthermia on glutamate release in ischemic penumbra after middle cerebral artery occlusion in rats. 797 7

In a series of 102 patients with angiographically proven cerebral sinus venous thrombosis (SVT) significant differences with arterial cerebrovascular disease were noted with respect to disease onset, reversibility of symptoms, occurrence of epileptic seizures and headache, cerebral blood flow under resting and stimulated conditions, occurrence of intracranial bleedings, and response to heparin therapy. From these findings pathophysiological differences are hypothesized: Whereas arterial cerebral ischemia usually is a monophasic abrupt thrombotic process and there is only a small penumbra, SVT is a continuing process of disequilibrium between prothrombotic and thrombolytic mechanisms; large areas of the brain are only functionally or metabolically disturbed but not irreversibly damaged. Intracranial bleeding in SVT is a consequence of increased venous and capillary pressure and thus occurs more frequently than in arterial thrombotic disease in which capillary pressure is reduced by the thrombosis and bleeding occurs during reperfusion of tissue damaged by ischemia. Heparin treatment in SVT is effective since it shifts the equilibrium away from the prothrombotic side and is able to save large areas of brain tissue that are only reversibly damaged. It improves venous outflow and thus decreases the risk of intracranial hemorrhage, in contrast with the arterial thrombotic disease where heparin increases the risk or at least the severity of intracranial bleedings.
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PMID:Pathophysiological aspects of cerebral sinus venous thrombosis (SVT). 801 60

Focal ischemia results in striking changes in gene expression. Induction of hsp72, a member of the family of 70 kDa heat shock/stress proteins is a widely studied component of the generalized cellular response to injury known as the 'stress response' that is detected in brain after ischemia and other insults. This overview summarizes observations on hsp72 expression in models of focal cerebral ischemia, considering its cellular distribution, factors affecting its transcriptional and translational expression, and its potential relevance to post-ischemic pathophysiology. Hsp72 expression is essentially limited to regions in which cerebral blood flow falls below 50% of control levels, provided that residual perfusion allows synthesis of the induced mRNA and protein. The cellular distribution of hsp72 depends on the nature of the ischemic insult, with preferential vascular expression in severely ischemic territory that is destined to necrose, pronounced neuronal expression throughout the ischemic 'penumbra', and limited glial involvement in a narrow zone immediately surrounding the infarct. Together with results in other injury models, these observations indicate that hsp72 induction identifies discrete populations of surviving cells that are metabolically compromised, but not irreversibly damaged after focal ischemia. Available evidence suggests that the stress response is an important component of cellular defense mechanisms, and that successful accumulation of hsp72 is critical to survival following ischemia. Its expression may also contribute to mechanisms of induced ischemic tolerance. Future studies may be expected to more fully characterize the range of altered gene expression in response to focal ischemic injury and to establish specific roles for hsp72 and other induced proteins in the progression of injury and recovery following such insults.
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PMID:The heat shock/stress response in focal cerebral ischemia. 802 4

We investigated immunohistochemically the localization and changes of copper/zinc superoxide dismutase (CuZn-SOD) and manganese superoxide dismutase (Mn-SOD) in the rat brain following 1 h of middle cerebral artery (MCA) occlusion. In normal brain, immunoreactivity to both SODs was observed in medium-sized neurons in the striatum and in many neurons in the neocortex. Mn-SOD was predominantly stained in cortical interneurons. The immunostaining of both SODs rapidly decreased or disappeared in neurons in the lateral segment of the striatum (ischemic center) 4 h after MCA occlusion, when the neurons were degenerating. Most neurons in the neocortex (ischemic penumbra) decreased their CuZn-SOD immunoreactivity but not Mn-SOD immunoreactivity 4 h after ischemia, when only a few neurons showed histopathological changes. CuZn-SOD immunoreactivity in almost all cortical neurons disappeared 1 day after ischemia, but Mn-SOD immunoreactivity was still preserved in interneurons, when cortical neurons showed typical pathological changes. Some cortical neurons in the boundary zone between normal and infarcted areas showed intense immunostaining to both SODs and glial SOD immunoreactivity appeared after 3 and 7 days. These results suggest that early loss of the scavenging system of free radicals may lead to neuronal damage after ischemic insult, and that induced SODs in the boundary zone between the normal and infarcted areas may act as a defense mechanism against damage.
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PMID:An immunohistochemical study of copper/zinc superoxide dismutase and manganese superoxide dismutase following focal cerebral ischemia in the rat. 805 37

We simultaneously measured neurotransmitter amino acids by the microdialysis technique and cortical CBF by laser-Doppler flowmetry in the ischemic penumbral cortex of rats subjected to 2-h normothermic (36.5-37.5 degrees C) transient middle cerebral artery (MCA) clip-occlusion. Brains were perfusion-fixed 3 days later and infarct volume measured. CBF (% of preischemic values) fell to 32 +/- 2% (mean +/- SD) during ischemia and rose to 157 +/- 68% during recirculation. Extracellular glutamate levels increased from a baseline value of 7 +/- 3 microM to a peak value of 180 +/- 247 microM 20-30 min following onset of ischemia but subsequently returned to near baseline levels after 70 min of ischemia despite ongoing MCA occlusion. The threshold CBF for moderate glutamate release was 48%. Massive glutamate release was seen during the first 60 min of MCA occlusion in the two animals showing the largest infarcts and occurred at CBF values < or = 20% of control levels. Mean CBF during ischemia exhibited an inverse relationship with infarct volume, and the magnitude of glutamate release during ischemia was positively correlated with infarct volume. Extracellular gamma-aminobutyrate and glycine changes were similar to those of glutamate but showed no significant correlation with infarct volume. These results suggest that (a) accumulation of extracellular glutamate is an important determinant of injury in the setting of reversible MCA occlusion and (b) reuptake systems for neurotransmitter amino acids may be functional in the penumbra during transient focal ischemia.
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PMID:Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: correlation with histopathology. 810 Feb 37

We studied whether administration of nitric oxide (NO) donors reduces the ischemic damage resulting from middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats (SHRs). In halothane-anesthetized and ventilated SHRs, the MCA was occluded. CBF was monitored using a laser-Doppler flowmeter. Three to five minutes after MCA occlusion, the NO donors sodium nitroprusside (SNP; 3 mg/kg/h) or 3-morpholino-sydnonimine (SIN 1; 1.5-6 mg/kg/h) were administered into the carotid artery for 60 min. As a control, the effect of papaverine (3.6 mg/kg/h), a vasodilator that acts independently of NO, was also studied. The hypotension evoked by these agents was counteracted by intravenous infusion of phenylephrine. At the end of the infusion, rats were allowed to recover. Stroke size was determined 24 h later in thionin-stained sections. In sham occluded rats, SNP (n = 5), SIN 1 (n = 5), and papaverine (n = 5) produced comparable increases in CBF (p > 0.05 from vehicle). After MCA occlusion, SNP (n = 5) and SIN 1 (n = 5), but not papaverine (n = 5), enhanced the recovery of CBF (p < 0.05 from vehicle) and reduced the size of the infarct by 28 +/- 12 and 32 +/- 7%, respectively (mean +/- SD; p < 0.05 from vehicle). To determine whether NO donors could act by inhibiting platelet aggregation, we studied the effect of SNP on collagen-induced platelet aggregation. Intracarotid administration of SNP (3 mg/kg/h for 60 min) did not affect platelet aggregation to collagen, suggesting that the protective effect of NO donors was not due to inhibition of platelet function. We conclude that NO donors increase CBF to the ischemic territory and reduce the tissue damage resulting from focal ischemia. The protective effect may result from an increase in CBF to the ischemic territory, probably the ischemic penumbra. These findings suggest that NO donors may represent a new therapeutic strategy for the management of acute stroke.
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PMID:Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. 811 18


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