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

Stroke is the second leading cause of death worldwide, and its incidence is expected to rise with the projected increase in the number of aging population. Disturbances of brain iron homeostasis have been linked to acute neuronal injury following cerebral ischemia. Free iron catalyzes the conversion of superoxide and hydrogen peroxide into hydroxyl radicals, which promote oxidative stress leading to subsequent cell death/apoptosis. In recent years, considerable evidence has emerged regarding the role of iron neurotoxicity following experimental cerebral ischemia. Few clinical studies have also attempted to investigate the role of iron in stroke patients. The present review will examine the currently available evidence for iron-mediated neurotoxicity and the potential mechanisms underlying deregulation of iron homeostasis in the brain following cerebral ischemia. Understanding the changes in brain iron metabolism and its relationship to neuronal injury in ischemic stroke could provide new therapeutic targets to improve the outcome of stroke patients.
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PMID:The role of iron neurotoxicity in ischemic stroke. 1523 Dec 41

In this study we investigated iron deposition in the hippocampus CA1 area and the corpus striatum pars dorsolateralis in a rat model of cerebral ischemia and ischemic tolerance. Forebrain ischemia was induced by four-vessel occlusion for 5-min as ischemic preconditioning. Two days after the preconditioning or the sham operation, a second ischemia was induced for 20-min. With the use of iron histochemistry, regional changes were examined after 2 to 8 weeks of recirculation following the 20-min ischemia with or without preconditioning. Perl's reaction with DAB intensification demonstrated iron deposits in the CA1 area and in the corpus striatum pars dorsolateralis after 2 weeks of recirculation. These iron deposits gradually increased in density and formed clusters by the 8th week. When the rats were exposed to 5-min ischemia 2 days before lethal 20-min ischemia, the deposition of iron in the CA1 region of the hippocampus and also in the corpus striatum pars dorsolateralis was decreased and produced a minimal number of iron-containing cells between the second and the 8th week of recirculation. Preconditioning with sublethal 5-min ischemia followed by 2 days of reperfusion also prevented the neuronal destruction of the hippocampal CA1 region induced by 20-min ischemia.
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PMID:The effect of preconditioning on the iron deposition after transient forebrain ischemia in rat brain. 1524 64

We examined the efficacy of the liposoluble iron chelator 2,2'-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1alpha (HIF-1alpha) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (+100%) and HIF-1alpha (-50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.
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PMID:Cytoprotective efficacy and mechanisms of the liposoluble iron chelator 2,2'-dipyridyl in the rat photothrombotic ischemic stroke model. 1528 Apr 35

Preconditioning of the brain by short-term ischemia increases brain tolerance to the subsequent severer ischemia. In this study, we investigated iron deposition in the cerebral cortex and the ischemic tolerance in a rat model of cerebral ischemia. Forebrain ischemia was induced by four-vessel occlusion for 5 min as ischemic preconditioning. Two days after preconditioning or after the sham-operation, the second ischemia was induced for 20 min. Changes in the cerebral cortex were examined after 1 to 8 weeks of recirculation following 20 min ischemia with or without preconditioning using the iron histochemistry. Granular deposits of the iron were found in the cytoplasm of the pyramidal cells in the layers III and V of the frontal cortex after 1 week of recirculation. When the rats were exposed to 5 min ischemia 2 days before 20 min lasting ischemia, the deposition of iron in the cytoplasm of the pyramidal cells in layers III and V of the frontal cortex was significantly lower during all periods of reperfusion. Preconditioning 5 min ischemia followed by 2 days of reperfusion before 20 min ischemia also prevented degeneration of the pyramidal neurons in layers III and V of the frontal cortex.
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PMID:Iron deposition in the brain following the ischemia in a rat model of ischemic tolerance. 1584 11

The aim of our study was to visualize developing vessel occlusion in focal cerebral ischemia in vivo. Cortical photothrombosis (PT) was induced in rats, which in addition received superparamagnetic iron oxide (SPIO) particles intravenously. When SPIO particles were applied simultaneously during illumination of the brain for induction of PT, animals showed a markedly hypointense cortical lesion on T2-weighted (T2-w) magnetic-resonance images (MRI). At 3 h after PT, this hypointense area was surrounded by a small hyperintense rim. At 48 h after PT the hyperintense rim had further extended, whereas the hypointense lesion core did not change in size or signal. On histological sections areas of signal loss on T2-w MRI corresponded to local accumulation of iron particles, which were trapped within vessel thrombi. When SPIO particles were applied at 2 h after PT, the lesion appeared hyperintense on T2-w MRI, but was surrounded by a small hypointense rim indicating ongoing vessel occlusion at its outer margins. In contrast, delayed SPIO application at 24 h after completion of PT produced a merely hyperintense cortical lesion on T2-w MRI. Correspondingly, no iron deposits were seen on tissue sections. In conclusion, early SPIO-enhanced MRI provides a reliable in vivo tool to delineate areas of developing vessel occlusion in experimental cerebral ischemia and identifies vessel thrombosis as one mechanism of secondary infarct growth in the PT paradigm. This new imaging technique may aid to evaluate antithrombotic treatment strategies in the future.
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PMID:In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI. 1591 47

Focal cerebral ischemia was induced in rats and followed with high-resolution MRI methods for a chronic period of 10 weeks. Two weeks after stroke induction and at the end of the observation period, conventional histological analysis was combined with immunohistochemical staining for macrophages and with Prussian blue staining for the detection of ferric iron. In the late chronic phase, a patchy hypointensity was observed in the ischemic caudoputamen exclusively on T2*-weighted (T2*W) images, with no change in quantitative T(1) and T(2) relaxation time maps. This characteristic MRI pattern is different from hemorrhagic transformations (HTs) at earlier time points (2 weeks post stroke induction), which became apparent on images of all three imaging sequences. The exclusive T2*-sensitive hypointensity colocalized with iron-positive macrophages in the lesion territory at this time. These iron-containing macrophages were found predominantly around blood vessels in the ischemic tissue, and interpreted as the result of a phagocytotic incorporation of red blood cells leaking from slowly degrading vessels. The present investigation demonstrates the sensitivity of heavily T2*W 3D MRI for observing the inflammatory response in the chronic phase after stroke, without prior systemic labeling of the blood-borne macrophages by iron oxide nanoparticles.
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PMID:MRI detection of macrophage activity after experimental stroke in rats: new indicators for late appearance of vascular degradation? 1596 79

Two different forms of cell death have been distinguished morphologically following cerebral ischaemia: necrotic and apoptotic cell death. The aim of this study was to investigate the contribution of apoptosis to ischaemic damage by carefully depicting the temporal and spatial neuronal death following focal ischaemia. For this purpose, rats were subjected to chemical photothrombosis, and histological and biochemical analyses were performed over a period of 24 h after the onset of ischaemia. In addition, the effects of the lipophilic antioxidant iron chelator 2,2'-dipyridyl (DP) were evaluated 24 h after photothrombosis when the lesion volume was maximal. Our results showed two separate waves of neuronal death. In the first wave, shrunken dark neurons were massively present as early as 2 h after photothrombosis in the infarct core. From this initial neuronal abnormal population, progressive and time-dependent changes of both necrotic and apoptotic cell death were observed, leading to ghost neurons and apoptotic bodies after 24 h. The extension of the lesion coincided with a second wave of cell death. Massive and rapid neuronal loss occurred at the infarct border, which appeared as a sharply demarcated pale region. Procaspase and poly(ADP-ribose) polymerase-1 (PARP-1) cleavages were also detected in the infarct core and surrounding damaged tissue. DP treatment markedly blocked the enlargement of the lesion, the infarct border being rescued from infarction. Furthermore, a large decrease of apoptotic bodies was associated with a significant drop of caspase and PARP-1 cleavages, suggesting that the protective effect of DP closely correlates with limitation of apoptosis expansion.
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PMID:Apoptotic cell death progression after photothrombotic focal cerebral ischaemia: effects of the lipophilic iron chelator 2,2'-dipyridyl. 1617 46

The immature brain is particularly susceptible to free radical injury because of its poorly developed scavenging systems and high availability of iron for the catalytic formation of free radicals. Neurons are more vulnerable to free radical damage than glial cells, but oligodendrocyte progenitors and immature oligodendrocytes in very prematurely born infants are selectively vulnerable to depletion of antioxidants and free radical attack. Reactive oxygen and nitrogen species play important roles in the initiation of apoptotic mechanisms and in mitochondrial permeability transition, and therefore constitute important targets for therapeutic intervention. Oxidative stress is an early feature after cerebral ischemia and experimental studies targeting the formation of free radicals demonstrate various degrees of protection after perinatal insults. Oxidative stress-regulated release of proapoptotic factors from mitochondria appears to play a much more important role in the immature brain. This review will summarize and compare with the adult brain some of the current knowledge of free radical formation in the developing brain and its roles in the pathophysiology after cerebral hypoxia-ischemia.
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PMID:Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. 1644 53

The mechanisms underlying functional recovery after stroke are poorly understood. Brain-adaptive responses to the hypoxic stress elicited by ischemia could contribute to these mechanisms. Indeed, hypoxia-inducible factor-1 (HIF-1), one of the main transcriptional factors regulated by oxygen level, increases the expression of several beneficial genes such as erythropoietin, glucose transporter-1 and vascular endothelial growth factor. In order to strengthen the expression of these hypoxia-inducible factors, we administered deferoxamine, an iron chelator known to stabilize HIF-1alpha protein expression, and examined its effects on the functional deficits induced by ischemia. Anesthetized Sprague-Dawley rats were subjected to 60 min of intraluminal occlusion of the middle cerebral artery. Chronic deferoxamine treatment (300 mg/kg, s.c.), or its vehicle, started 24 h after ischemia and was continued bi-weekly until the animals were killed. Sensorimotor deficits were periodically assessed over 2 months, and at this end point, the lesion volume was determined by histology. Treatment with deferoxamine significantly decreased the size of brain damage (-28%) after ischemia and improved behavioral recovery. Indeed, neurological score and sensorimotor performances in the adhesive removal test recovered earlier in the deferoxamine-treated animals. Moreover, the long-lasting skilled forepaw reaching deficits were attenuated by deferoxamine. Although an antioxidant effect of deferoxamine cannot be excluded, the hypothesis that its beneficial effects could be mediated by an increase in HIF-1 target genes merits further investigations. Our data suggest that delayed administration of deferoxamine could represent an interesting therapeutical approach to treat focal cerebral ischemia.
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PMID:Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat. 1662 32

Increasing evidence demonstrates that oxidative stress plays an important role in brain injury in experimental models of brain ischemia. Thymoquinone, the main constituents of the volatile oil from Negella sativa seeds, is reported to possess strong antioxidant properties. Hence, the present study was undertaken to evaluate the neuroprotective effect of thymoquinone against transient forebrain ischemia-induced neuronal damage in the rat hippocampus. Rats were divided randomly into five groups: control, sham, ischemia, thymoquinone and ischemia+thymoquinone. Transient forebrain ischemia was induced with bilateral occlusion of both common carotid arteries for 10 min followed by 7 days of reperfusion. Thymoquinone was administered (5 mg/kg/day p.o.) 5 days before ischemia and continued during the reperfusion time. Animals were sacrificed, and brain tissues were isolated for histopathological examination. Hippocampal tissues were also used for determination of malondialdehyde levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant and the activities of the antioxidant enzymes catalase and superoxide dismutase (SOD). Thymoquinone and its metabolite thymohydroquinone were tested as inhibitors of the in vitro non-enzymatic lipid peroxidation induced by iron-ascorbate in the hippocampal homogenate. Forebrain ischemia-reperfusion neural injury in rats was demonstrated by histopathological observation, which revealed significant neural cell death in the hippocampus CA1 area 7 days post-ischemia (77% cell loss). Additionally, forebrain ischemia-reperfusion oxidative injury in rats was demonstrated by a significant increase in malondialdehyde and a significant decrease in GSH contents, catalase and SOD activities in the hippocampal tissue compared to the control or sham-operated groups. Pretreatment of thymoquinone attenuated forebrain ischemia-induced neuronal damage manifested by significantly decreasing the number of dead hippocampal neuronal cells (24% in thymoquinone-treated versus 77% for ischemia, P<0.001), which confirm the protective role of thymoquinone in ischemia-reperfusion injury. Also, pretreatment of ischemic rats with thymoquinone decreased the elevated levels of malondialdehyde and increased GSH contents, catalase and SOD activities to normal levels. Thymoquinone and thymohydroquinone inhibited the in vitro non-enzymatic lipid peroxidation in hippocampal homogenate induced by iron-ascorbate. The IC50 for thymoquinone and thymohydroquinone were found to be 12 and 3 microM respectively. This suggests that the protection of thymoquinone and its metabolite involve increased resistance to oxidative stress. In conclusion, thymoquinone is effective in protecting rats against transient forebrain ischemia-induced damage in the rat hippocampus. This spectacular protection makes thymoquinone a promising agent in pathologies implicating neurodegenaration such as cerebral ischemia.
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PMID:Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. 1682 80


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