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

Cerebral artery occlusion produces regions of incomplete ischemia (the ischemic penumbra), which, in the absence of reflow, undergo progressive metabolic deterioration culminating in infarction. The factors causing infarction are not yet established, but progression to cell death is preceded by progressive acidosis, decreasing glucose utilization, and ATP depletion. To identify potential mechanisms of glial death in the ischemic penumbra, astrocytes in culture were subjected to conditions that occur during incomplete ischemia: hypoxia, acidosis, and raised extracellular K+. Neither acidosis (to pH 6.2) nor chemical hypoxia (5 mM azide) alone produced significant astrocyte death or marked ATP depletion. By contrast, hypoxia combined with acidosis caused near-complete ATP depletion by 3.5 h and 70% cell death after 7 h. Glycolytic rate increased during hypoxia alone but decreased during hypoxia with acidosis. Since glycolysis is the sole source of ATP production during hypoxia, acidosis inhibition of glycolysis is a likely cause of the far greater ATP depletion resulting from hypoxia with acidosis. Glutamate uptake was reduced during hypoxia and further reduced during hypoxia with acidosis, consistent with the changes in astrocyte ATP. Glutamate uptake, ATP levels, and glycolytic rate each exhibited reductions that were progressive over 3 h of hypoxia with acidosis, and these changes were accompanied by progressive intracellular acidosis. Since ATP depletion leads to acidosis, and acidosis inhibits glycolysis, these findings suggest a regenerative cycle initiated by the combination of hypoxia with acidosis. This cycle could result in progressive metabolic decline and cell death in the ischemic penumbra.
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PMID:Astrocyte energetics, function, and death under conditions of incomplete ischemia: a mechanism of glial death in the penumbra. 929 57

Transient middle cerebral artery occlusion in rats leads to infarction of the lateral part of the striatum and adjacent neocortex, with selective neuronal necrosis in the bordering penumbral zones. Administration of glutamate, cytokine, and leukocyte antagonists have rescued mainly neocortical neurons, indicating differences in the degenerative processes. The aim of this study was, therefore, to describe the microglial/macrophage activation and polymorphonuclear leukocyte recruitment patterns and to correlate these with the ischemia-induced degenerative processes. The analysis showed significant differences in the characteristics and timing of the microglial/macrophage responses between the caudate putamen and neocortical infarct zones, the infarct zones and their associated penumbral zones, as well as between the striatal and the neocortical penumbral zone. Infiltrations with polymorphonuclear leukocytes into the infarct zones were limited and shortlasting and confined to the acutely degenerating striatum and piriform cortex. A delayed, massive infiltration with lipid phagocytes into the caudate putamen infarct markedly contrasted an early recruitment and activation of microglia/macrophages in the adjacent penumbra. Within the neocortex, a later onset of degeneration along the insular-parietal axis was marked by neuronal expression of heat shock protein and a progressive microglial activation with induction of the full repertoire of microglial activation markers, including a widespread microglial major histocompatibility complex (MHC) class II antigen expression. We interpret the present results as delineating two differentially progressing penumbral zones, which are likely to reflect differences in the underlying degenerative processes. Differences in the microglial/macrophage activation pattern attract special attention, as these cells may constitute specific targets for therapeutic intervention.
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PMID:Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion. 930 29

Recirculation following 2 h of focal ischemia due to transient middle cerebral artery (MCA) occlusion has previously been found to be accompanied by an initial, partial recovery of the cellular bioenergetic state and of mitochondrial respiratory functions, with secondary deterioration during the first 2-4 h of reflow. Both the free radical spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) and the immunosuppressant drug FK506 ameliorate the damage incurred by the 2-h period of focal ischemia, even when given 1-3 h after the start of the recirculation. The primary objective of this study was to find out if FK506, like PBN, prevents the secondary deterioration of mitochondrial function, as this can be studied in vitro. Since this proved to be the case, we addressed the question of whether the secondary mitochondrial dysfunction and bioenergetic failure were related to a secondary compromise of microcirculation and cellular oxygen delivery. Six groups of male Wistar rats were studied for measurement of mitochondrial respiratory activity (total, n = 36). One group was used as control (n = 6). In the other groups of animals, MCA occlusion of 2 h duration was induced by an intraluminal filament technique, Neocortical focal and perifocal ("penumbra") tissues were sampled after 2 h of ischemia (n = 6) and after 1 h (n = 6), 2 h (n = 6 with vehicle), and 4 h (n = 6 with vehicle; n = 6 with FK506) of recirculation. The vehicle or 1.0 mg.kg-1 of FK506 was injected intravenously after 1 h of recirculation. Homogenates were prepared, and stimulated (+ADP), nonstimulated (-ADP), and uncoupled respiratory rates were measured polarographically. The uncoupling agent used was carbonyl cyanide m-chlorophenylhydrazone. Local CBF and tissue oxygen tension were evaluated by laser-Doppler flowmetry and PO2 microelectrodes, respectively, throughout the whole periods of 2 h of ischemia and 4 h of recirculation, using a remote MCA occlusion technique. After 2 h of ischemia, the penumbra showed a moderate decrease and the focus a marked decrease in ADP-stimulated and uncoupled respiratory 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. The secondary deterioration was prevented by FK506. The results thus confirm previous findings showing that secondary mitochondrial dysfunction occurs following transient focal cerebral ischemia and demonstrate that FK506, like PBN, improves the in vitro performance of mitochondria in focal and penumbral areas. Following MCA occlusion, local CBF in a penumbral area and tissue PO2 in a focal area decreased to about 30 and 5% of control, respectively. However, recirculation brought about rapid recovery of blood flow and oxygen delivery. During the whole 4-h period of recirculation, local CBF and tissue PO2 were maintained close to 100% and at about 160% of the preischemic level, respectively. The results make it highly unlikely that the secondary bioenergetic failure during recirculation is due to a compromised microcirculation. It follows that oxygen delivery is not rate-limiting for recovery events. Very likely, FK506 (and PBN) acts at the cellular level to improve mitochondrial energy functions.
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PMID:The immunosuppressant drug FK506 ameliorates secondary mitochondrial dysfunction following transient focal cerebral ischemia in the rat. 936 6

The role of calcium-activated proteolysis in hypoxic neuronal injury was investigated using an in vitro slice model of moderate hypoxia that mimics many features of an ischemic penumbra. The calpain inhibitor, MDL28170, significantly improved the recovery of synaptic responses in hippocampal slices following prolonged, moderate hypoxia without hypoxic depolarization. This finding further implicates calpain-mediated proteolysis in the development of neuronal injury following moderate metabolic challenge such as occurs in regions of partial ischemia.
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PMID:Neuronal recovery after moderate hypoxia is improved by the calpain inhibitor MDL28170. 937 90

The authors studied the effects of pre- and postischemic administration of dizocilpine maleate (MK-801) on collateral and regional cerebral blood flow (CBF). The ischemic penumbra appears to benefit most from the neuroprotective effects of MK-801. The precise mechanism by which MK-801 provides this neuroprotection remains controversial. Alterations in CBF have been demonstrated with MK-801 administration, but whether the response is an increase or decrease in flow has remained unclear. A left-sided craniectomy was performed in 20 dogs. A branch of the middle cerebral artery (MCA) was cannulated and collateral blood supply-dependent tissue (CDT) was identified using the "shadow flow" technique. Regional CBF was measured using radiolabeled microspheres. Six dogs received MK-801 (1 mg/kg administered intravenously) before they underwent MCA branch occlusion; the remaining 14 dogs received MK-801 after they underwent MCA occlusion. Cerebral blood flow and vascular pressures were measured 30 and 60 minutes after MK-801 administration. In animals that received MK-801 before MCA occlusion, CBF did not change significantly from baseline values before or after occlusion. In contrast, in animals that received MK-801 after MCA occlusion, CBF was significantly reduced in all regions of the brain, including the CDT. Collateral blood supply-dependent tissue showed a 51.7% reduction in flow, whereas normal CBF was reduced by 29.7%. The MK-801 induced cerebral vasoconstriction in both groups. The neuroprotective effects of MK-801 do not appear to be caused by the augmentation of collateral or global cerebral circulation and, in fact, may block the glutamate-mediated vasodilation that occurs during ischemia.
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PMID:Pre- and postischemic effects of the NMDA receptor antagonist dizocilpine maleate (MK-801) on collateral cerebral blood flow. 938 6

Oxygen free radicals are postulated to participate in the pathogenesis of ischemic brain injury. The present study investigated the response of the endogenous antioxidant enzyme, superoxide dismutase (SOD), in a model of transient focal ischemia in the rat neocortex. SOD activity was increased significantly in the penumbra region at 6-24 h postischemia, while no significant changes in SOD activity were observed in either the core region or striatum. These results indicate that endogenous antioxidant activity is differentially affected by the intensity of ischemic challenge and suggest that the regional effects of oxygen free radicals may vary substantially following ischemia-reperfusion.
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PMID:Differential induction of superoxide dismutase in core and penumbra regions after transient focal ischemia in the rat neocortex. 938 88

Using autoradiographic image-averaging strategies, we studied the relationship between local glucose utilization (LCMRglc) and blood flow (LCBF) in a highly reproducible model of transient (2-hour) middle cerebral artery occlusion (MCAO) produced in Sprague-Dawley rats by insertion of an intraluminal suture coated with poly-L-lysine. Neurobehavioral examination at 60 minutes after occlusion substantiated a high-grade deficit in all animals. In two subgroups, LCBF was measured with 14C-iodoantipyrine at either 1.5 hours of MCAO, or at 1 hour of recirculation after suture removal. In two other matched subgroups, LCMRglc was measured with 14C-2-deoxyglucose at 1.5 to 2.25 hours of MCAO, and at 0.75 to 1.5 hours of recirculation after 2 hours of MCAO. Average image data sets were generated for LCBF, LCMRglc, and the LCMRglc/LCBF ratio for each study time. Middle cerebral artery occlusion for 2 hours induced graded LCBF decrements affecting ipsilateral cortical and basal ganglionic regions. After 1 hour of recirculation, LCBF in previously ischemic neocortical regions increased by 40% to 200% above ischemic levels, but remained depressed, on average, at about 40% of control. By contrast, frank hyperemia was noted in the previously ischemic caudoputamen. Mean cortical LCBF values during MCAO correlated highly with their respective LCBF values after 1 hour of recirculation (R = 0.93), suggesting that post-ischemic LCBF recovery is related to the depth of ischemia. Despite focal ischemia, LCMRglc during approximately 2 hours of MCAO was preserved, on average, at near-normal levels; but following approximately 1 h of recirculation, LCMRglc became markedly depressed (on average, 55% of control in previously densely ischemic cortical regions). Regression analysis indicated that this depressed glucose utilization was determined largely by the intensity of antecedent ischemia. By pixel analysis, the ischemic core (defined as LCBF 0% to 20% of control) comprised 33% of the ischemic hemisphere, and the penumbra (LCBF 20% to 40%) accounted for 26%. The penumbra was concentrated at the coronal poles of the ischemic lesion and formed a thin shell around the central ischemic core. During 2 hours of MCAO, the LCMRglc/LCBF ratio within the ischemic penumbra was increased four-fold above normal (average, 179 umol/100 mL). In marked contrast, after approximately 1 h recirculation, this uncoupling had almost completely subsided. The companion study (Zhao et al., 1997) further analyzes these findings in relation to patterns of infarctive histopathology.
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PMID:Transient middle cerebral artery occlusion by intraluminal suture: I. Three-dimensional autoradiographic image-analysis of local cerebral glucose metabolism-blood flow interrelationships during ischemia and early recirculation. 939 26

We conducted a pixel-based analysis of the acute hemodynamic and metabolic determinants of infarctive histopathology in a reproducible model of temporary (2-hour) middle cerebral artery occlusion (MCAO) produced in rats by an intraluminal suture. Three-dimensional averaged image data sets of local cerebral blood flow (LCBF) and glucose utilization (LCMRglc) acquired in the companion study (Belayev et al., 1997) either at the end of a 2-hour period of MCAO or after 1 hour of recirculation were comapped (using digitized atlas-templates) with data sets depicting the frequency of histological infarction in a matched animal group (n = 8) in which 2 hours of MCAO was followed by 3-day survival, sequential neuro behavioral examinations, and perfusion-fixation and paraffin-embedding of brains for light-microscopic analysis. All rats developed marked postural-reflex and forelimb-placing deficits at 60 minutes of MCAO, signifying high-grade ischemia. Tactile placing deficits persisted during the 72-hour observation period while visual placing and postural-reflex abnormalities variably improved. Comapping of LCBF and histopathology showed that in those pixels destined to undergo infarction, LCBF measured at 2 hours of MCAO showed a sharp distributional peak centered at 0.14 mL/g/min. In 70% of pixels destined to infarct, LCBF at 2 hours of MCAO was 0.24 mL/g/min or below, and in 89% LCBF was below 0.47 mL/g/min (the upper limits of the ischemic core and penumbra, respectively, as defined in the companion study [Belayev et al., 1997]). Local cerebral glucose utilization measured at approximately 1 hour after 2 hours of MCAO was distributed bimodally in the previously ischemic hemisphere. The major peak, at 22 mumol/100g/min, coincided exactly with the distribution peak of pixels destined to undergo infarction, while in pixels with a zero probability of infarction, LCMRglc was higher by 12 to 13 mumol/100g/min. These results indicate that local blood flow at 2 hours of MCAO is a robust predictor of eventual infarction. Pixels with ischemic-core levels of LCBF (0% to 20% of control) have a 96% probability of infarction, while the fate of the penumbra is more heterogeneous: below LCBF of 0.35 mL/g/min, the probability of infarction is 92%, while approximately 20% pixels in the upper-penumbral LCBF range (30% to 40% of control) escape infarction. Our data strongly support the view that the likelihood of infarction within the ischemic penumbra is highly influenced by very subtle differences in early perfusion.
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PMID:Transient middle cerebral artery occlusion by intraluminal suture: II. Neurological deficits, and pixel-based correlation of histopathology with local blood flow and glucose utilization. 939 27

Focal ischemia in the parietal cortex of the rat results in massive neuronal death in the infarct zone and penumbra between 12 hours and 6 days after photothrombosis. To examine a possible role of Bcl-2 family proteins in this process of cell death, we investigated their expression by immunoblot assays and immunocytochemistry, and correlated expression patterns with TUNEL as well as morphological signs indicative of apoptosis. In the center of the lesion Bax immunostaining was increased in many degenerating neurons between 4 hours and 3 days after the induction of photothrombosis. At all time points examined, Bcl-2 and Bcl-X protein levels were markedly reduced in injured neurons as compared to the unlesioned side. At the border of the ischemic lesion, two areas were distinguished: 1 - 2 days after induction of photothrombosis, pyknotic cells located immediately adjacent to the lesion core displayed nuclear Bcl-X and Bax immunoreactivity. In contrast, large, morphologically intact neurons located more towards the healthy brain parenchyma displayed an increase in cytoplasmic Bcl-2 and Bcl-X proteins. Double staining for each of the Bcl-2 family proteins and TUNEL revealed that DNA strand breaks and nuclear fragmentation seen in cells located in the lesion core were often associated with increased levels of Bax, but not with elevated Bcl-2 or Bcl-X protein levels, suggesting a role for Bax in the induction of apoptotic death in these cells. The upregulation of Bcl-2 and Bcl-X expression in surviving neurons close to the penumbra might reflect an active survival mechanism that protects these neurons from cell death following a sublethal insult.
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PMID:Differential regulation of Bax, Bcl-2, and Bcl-X proteins in focal cortical ischemia in the rat. 945 66

Thioredoxin (TRX) is a small, multifunctional protein with a redox-active site and multiple biological functions that include reducing activity for reactive oxygen intermediates. We assayed TRX and TRX mRNA by immunohistochemical methods and hybridization experiments in the rat brain after middle cerebral artery (MCA) occlusion. During ischemia, the immunoreactivity for TRX decreased; it disappeared after MCA occlusion in the ischemic regions. It rapidly decreased and nearly disappeared at 4 and 16 hours after MCA occlusion in the lateral striatum and frontoparietal cortex, respectively. On the other hand, in the perifocal ischemic region, the penumbra, TRX immunoreactivity began to increase 4 hours after MCA occlusion and continued to increase until 24 hours after occlusion. In hybridization experiments, TRX mRNA decreased and nearly disappeared 4 hours after MCA occlusion in the lateral striatum. In the frontoparietal cortex, it decreased until 24 hours after MCA occlusion. In the perifocal ischemic region, TRX mRNA began to increase 4 hours after MCA occlusion and continued to increase until 24 hours. Northern blot analysis showed that total TRX mRNA in the operated hemispheres was induced from 8 hours and increased until 24 hours after the surgical procedures. We previously reported that recombinant TRX promotes the in vitro survival of primary cultured neurons. We now suggest that TRX in the penumbra has neuroprotective functions and that decreased levels of TRX in the ischemic core modify neuronal damage during focal brain ischemia.
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PMID:Redox control of neuronal damage during brain ischemia after middle cerebral artery occlusion in the rat: immunohistochemical and hybridization studies of thioredoxin. 946 64


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