Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nestin is an intermediate filament protein, transiently and abundantly expressed early in embryogenesis, e.g., in neuroepithelial cells, radial glia, germinal matrix cells and vascular cells. In the adult rat brain, nestin is only present in endothelial and select subventricular cells. We tested the hypothesis that after an experimental stroke, nestin expression is induced in glial cells and neurons. We measured the temporal profile of nestin expression after induction of focal cerebral ischemia in adult rats. Brain from rats (n=24) subjected to 2 h of transient middle cerebral artery occlusion (MCAo) and 3 h, 6 h, 12 h, 1 day, 2 days, 3 days, 7 days and 28 days (n=3, per time point) of reperfusion, and control sham operated (n=3) rats were processed for Western blotting to quantify nestin. Another set of brains from rats (n=28), subjected to 2 h of MCAo and 6 h, 12 h, 2 days, 7 days, 14 days, 21 days, and 28 days (n=4, per time point, except n=8 at 2 days) of reperfusion, and control sham operated (n=3) and normal (n=2) rats were processed by single and double labeled immunohistochemistry for cellular identification of nestin expression. By Western blotting, nestin within ischemic tissue increased slightly as early as 6 h, peaked at 7 days, and expression persisted for at least 4 weeks after 2 h of MCAo. By immunohistochemistry, nestin was expressed in astrocytes in the ischemic core from 6 to 12 h after MCAo. Nestin immunoreactivity was present in large numbers of astrocytes, and in scattered oligodendroglia and monocytes/macrophages in both the inner and outer boundary zones to the ischemic core at 1-7 days after MCAo. Nestin expression in glial cells declined at longer durations of survival, although for least 4 weeks after MCAo the nestin immunoreactivity delineated the boundary zone adjacent to the ischemic core. Nestin expression was present in some neurons localized to the outer boundary zone of the ischemic lesion in the cortex and striatum, and in most ependymal cells in the ventricular and subventricular zone (VZ/SVZ) from day 2 after MCAo and onward. The expression of nestin increased throughout the microvasculature in both the ischemic core and the boundary zone in all ischemic rats after 12 h of reperfusion. After stroke, nestin immunoreactivity in glial, neuronal and ependymal cells is suggestive of a protein expression pattern found in developing brain.
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PMID:Temporal profile of nestin expression after focal cerebral ischemia in adult rat. 1044 10

Cell culture studies have established SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) as an important factor in growth factor and cytokine-activated signaling pathways. However, the significance of SHP2 in the mammalian central nervous system (CNS) is not known since early embryonic lethality occurs in shp2 null mice. To bypass this embryonic lethality, transgenic animals containing a catalytically inactive mutant of SHP2 (SHP2-CS) under the control of a nestin intron II/thymidine kinase minimal promoter were generated. In the developing CNS of these animals, although high-level transgene expression was detected in the neuroepithelium, there was no obvious abnormality in progenitor cell proliferation or migration. In the adult brain, high-level transgene expression was detected in the subventricular zone, rostral migratory stream, dentate gyrus of hippocampus, and cerebellum. Because SHP2 function is likely important in cell survival pathways, we used a focal cerebral ischemia model to examined whether SHP2 is important during CNS injury. Ischemia-induced damage and neuronal death was found to be significantly greater in nestin-SHP2-CS mice than in wild-type littermates. These findings indicate that SHP2 is a required factor in signaling pathway(s) important for neuronal survival.
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PMID:Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2. 1102 80

Immunohistochemistry and double immunofluorescent labeling techniques combined with confocal laser scanning microscope analysis were used to investigate the characteristic spatial induction profile of nestin following a transient middle cerebral artery occlusion in adult rat brain. The results showed that nestin was induced in ischemic core at 1 day after reperfusion. In addition to ischemic core, the expression of nestin increased in peri-ischemic I, II and III regions at 3 days and 1 week, then it decreased and narrowed along the rim of ischemic core 2 weeks after reperfusion. Double immunofluorescent labeling showed that nestin positive cells were mostly co-stained with GFAP,a astrocyte marker, in peri-ischemic I region 3 days after reperfusion. At 2 weeks, however nestin cells showed a long process and the cells double stained with nestin and NSE,a neuonal specific marker,increased in the ischemic brain. The results suggest that cerebral ischemia induces nestin expression in damaged neurons which might favor the neuroprotection against ischemic damage.
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PMID:[The expression of nestin in ischemia-injured brain of adult rat]. 1219 76

Expression levels of mRNA are commonly measured as a ratio of test to reference gene. The assumption is that reference genes such as beta-actin or cyclophilin are unaffected by treatment and act as steady-state controls. TaqMan real-time RT-PCR was used to test these assumptions in a rat model of cerebral ischaemia (tMCAO). Following measurement of 24 genes, we show that reference genes in this animal model fail the criteria for steady-state controls. Neuronal loss, glial proliferation and an influx of leukocytes into the lesioned brain result in major disturbance to cell populations. The mRNA for reference genes, as for test genes, reflects these changes. Specific mRNA levels vary according to the choice of reference gene to which they are normalised. In the process of resolving reference gene issues, mRNA increases were discovered for leukaemia inhibitory factor, nestin and galanin in rat brain hemispheres affected by ischaemia. Results are reported for a further 21 genes and mathematical and statistical methods are described that allow in this study fraction-fold changes in mRNA to be detected.
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PMID:The quantification of gene expression in an animal model of brain ischaemia using TaqMan real-time RT-PCR. 1239 70

Cell replacement therapy may have the potential to promote brain repair and recovery after stroke. To compare how focal cerebral ischemia affects the entry, migration, and phenotypic features of neural precursor cells transplanted by different routes, we administered neuronal precursors from embryonic cerebral cortex of green fluorescent protein (GFP)-expressing transgenic mice to rats that had undergone middle cerebral artery occlusion (MCAO) by the intrastriatal, intraventricular, and intravenous routes. MCAO increased the entry of GFP-immunoreactive cells, most of which expressed neuroepithelial (nestin) or neuronal (doublecortin) markers, from the ventricles and bloodstream into the brain, and enhanced their migration when delivered by any of these routes. Transplanted neural precursors migrated into the ischemic striatum and cerebral cortex. Thus, transplantation of neural precursors by a variety of routes can deliver cells with the potential to replace injured neurons to ischemic brain regions.
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PMID:Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. 1568 65

The intermediate filament nestin is upregulated in response to cerebral ischemia; the significance of this, however, is incompletely understood. Here, we used transgenic mice that express green fluorescent protein (GFP) under control of the nestin promotor to characterize the fate of nestin-expressing cells up to 8 weeks after 30 mins occlusion of the middle cerebral artery (MCAo) and reperfusion. The population of nestin-GFP+ cells increased in the ischemic lesion rim and core within 4 days, did not become TUNEL-positive, and was detectable up to 8 weeks in the lesion scar. Nestin-GFP+ cells proliferated in situ and underwent approximately one round of cell division. They were not recruited in large numbers from the subventricular zone (SVZ) as indicated by absence of colabeling with intracerebroventricularly injected dye DiI in the majority of nestin-GFP+ cells. Nestin-GFP+ cells expressed the chondroitin sulfate proteoglycan NG2 and nestin protein, but typically lacked mature astrocytic markers, that is, glial fibrillary acid protein (GFAP) or S100beta. Vice versa, the majority of GFAP+ cells lacked nestin-expression and surrounded the ischemic lesion by 4 days. Whole-cell patch-clamp recordings in acute brain slices from controls showed that only about half of nestin-GFP+ cells displayed complex membrane properties. In contrast, 4 days after the insult all nestin-GFP+ cells expressed these properties. We hypothesize that the change in physiologic properties induced by the ischemic insult is directed toward a specific function of nestin-expressing cells.
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PMID:Nestin-expressing cells divide and adopt a complex electrophysiologic phenotype after transient brain ischemia. 1595 63

This study addresses whether hippocampal progenitor cells express nestin following cerebral ischemia in rats. Cell counts within the hippocampal hilus were significantly greater following severe (eight-vessel occlusion) ischemia than following intermediate (four-vessel occlusion) ischemia (1527+/-87/mm2 vs. 918+/-71/mm2). Bromedeoxyuridine-positive cell counts were significantly higher with severe ischemia than with intermediate ischemia or in sham-operated animals, respectively (368+/-45, 43+/-14 and 7+/-1/mm2). In the eight-vessel occlusion group, 47+/-8/mm2 bromedeoxyuridine-labeled cells expressed nestin, significantly higher than in the four-vessel occlusion group and sham-operated animals (1+/-1 and 1+/-0/mm2, P<0.01 vs. eight-vessel occlusion, respectively). Confocal microscopy verified that a subset of the bromedeoxyuridine-positive cells expressed nestin. In conclusion, severe ischemia elicits nestin expression in hippocampal progenitor cells in rats.
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PMID:Hippocampal progenitor cells express nestin following cerebral ischemia in rats. 1614 41

An important cellular event associated with reduced structural and functional recovery after stroke in aged animals is the early formation of a scar in the infarcted region that impairs neural recovery and repair. Despite the detrimental impact of infarct scar formation, the brain regions and cell types that supply the components of the scar are not well characterized. We hypothesized that premature cerebral scar formation in aged animals is associated with an altered cellular response to cerebral ischemia. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3 month- and 20 month-old male Sprague Dawley rats. After 3, 7, 14, and 28 days, brain tissue was subjected to real-time reverse-transcriptase-PCR (RT-PCR) and immunostaining for 1) a cellular proliferation marker (BrdU); 2) a neuroepithelial marker (nestin); 3) an astrocytic marker (glial fibrillary acidic protein [GFAP]); 4) a neuronal marker, doublecortin; and 5) a basal lamina marker (laminin), and analyzed using 3D-reconstruction of confocal images. In this model the infarct was localized primarily in the parietal cortex. By RT-PCR there was a robust increase in nestin mRNA transcripts shortly after stroke, and this increase was particularly intense in aged rats. Accordantly, we found in aged rats a rapid delimitation of the infarct area by nestin-positive cells and an early incorporation of these cells into the glial scar. The capillaries of the corpus callosum were the major source of proliferating, nestin-positive cells, many of which were also immunoreactive for doublecortin, although a smaller population of nestin cells were associated with the ventricular walls. Despite the proliferation of nestin cells, they did not make a significant contribution to neurogenesis in the infarcted cortex, possibly because the corpus callosum impedes the migration of subventricular zone-derived nestin-positive cells into the lesioned area. We conclude that: (i) the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic reaction to cerebral insult is accelerated in aged animals; (ii) the proliferating cells contribute to the formation of the glial scar, but few of the cells appear to become neurons; and (iii) the vasculature plays a hitherto unrecognized role as a source of proliferating cells after stroke. Because capillary-derived cells help to form the glial scar, elucidating the molecular basis of this phenomenon and its acceleration in the aging brain could yield novel approaches to enhancing neurorestoration in the elderly.
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PMID:Accelerated delimitation of the infarct zone by capillary-derived nestin-positive cells in aged rats. 1647 21

Cerebral ischemia evokes changes in gene expression time-dependently after the ischemic event. Most studies on transcriptional changes following ischemia have centered on relatively early postischemic time points, and detected multiple genes relevant to neuronal cell death. However, functional outcome after ischemia depends critically on adaptations of the postischemic brain. Plasticity may derive from network-inherent changes, or from the formation of new nerve cells in the CNS. We have screened for gene expression changes up to 3 weeks following a limited photothrombotic cortical insult in the rat sensorimotor cortex by using the sensitive restriction-mediated differential display (RMDD) technique. A high number of genes were detected as induced at early or intermediate time points in the ipsi- and contralateral cortex (6 and 48 h). Unexpectedly, at the late time point examined (3 weeks), we still detected 40 genes that were changed in their expression. We further characterized the expression of two genes linked to neurogenesis (nestin and stathmin), and two genes likely involved in reconfiguring neuronal networks (semaphorin VIa and synaptotagmin IV). Conclusively, our data highlight the degree of long-term transcriptional changes in the cortex after ischemia, and provide insight into functional pathways of relevance for compensatory recovery mechanisms in neural networks.
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PMID:Long-term gene expression changes in the cortex following cortical ischemia revealed by transcriptional profiling. 1653 Jan 83

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular mechanisms underlying such phenomena are not known. Using BrdU-labeling, quantitative immunohistochemistry and 3D-reconstruction of confocal images in a rat model of mild cerebral ischemia, we found that aged rats are highly susceptible to develop an early infarct that is associated with premature cellular proliferation originating from the vascular tree. In aged rats we also found a rapid delimitation of the infarct area by capillary-derived neuroepithelial cells and an early incorporation of these cells into the glial scar. Since most proliferating cells at the infarct site are microglia or nestin-positive cells derived from the vascular wall, we conclude that the vasculature plays a hitherto unrecognized role as a source of proliferating neuroepithelial cells after stroke. Age-associated alterations in the timing and origin of the cytogenic response to cerebral ischemia may underlie the poor functional recovery from stroke. Clarifying the molecular basis of these phenomena could yield novel approaches to enhancing neurorestoration in the elderly. Studies of stroke in experimental animals have demonstrated the neuroprotective efficacy of a variety of interventions, but most of the strategies that have been clinically tested failed to show benefit in aged humans. One possible explanation for this discrepancy between laboratory and clinical investigations is the role that age plays in the recovery of the brain from insult. Although it is well known that aging is a risk factor for stroke (Barnett HJ, 2002), the majority of experimental studies of stroke have been performed on young animals, and therefore may not fully replicate the effects of ischemia on neural tissue in aged subjects (Wang LC et al., 1995; Davies M et al., 1995; Sutherland GR et al., 1996; Popa-Wagner A et al., 1998, 1999a). Hence, the aged post-acute animal model is clinically most relevant to stroke rehabilitation and cellular studies (Lindner MD et al., 2003; Brown AW et al., 2003; Badan I et al., 2003).
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PMID:Premature cellular proliferation following cortical infarct in aged rats. 1730 79


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