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

Regarding regenerative strategies early post-ischemic therapeutic interventions might have a great impact on further pathophysiological cascades. To understand the early post-ischemic events we analyzed proliferation and neurogenesis as early as on day 3 after transient global ischemia in rats. Evaluations were performed not only in the dorsal hippocampus, where post-ischemic cell death develops selectively in the cornu ammonis, subfield 1 area, but also in distant areas like the ventricle wall and the striatum. Ischemia was induced by a transient two-vessel occlusion combined with hypotension. Animals received daily i.p. injections of 5-bromo-2-deoxyuridine until decapitation 1 or 3 days after ischemia. Immunohistochemistry was performed to detect 5-bromo-2-deoxyuridine and co-labeling with cell-specific markers. Three days after ischemia, proliferation significantly increased throughout the forebrain. Early neurogenesis, detected by doublecortin labeling, on the other hand, was restricted to the neurogenic zones of the dentate gyrus and the lateral ventricle. Global ischemia reduced the overall number of doublecortin-positive cells in the dentate gyrus, particularly in the upper blade of the dentate gyrus. However, the number of newly generated doublecortin- and 5-bromo-2-deoxyuridine double-labeled cells was unchanged. The vast majority of newly generated cells were microglia/macrophages, which invaded morphologically damaged as well as undamaged regions. Astroglial cells were activated all over the forebrain by the ischemic insult. They were co-localized almost completely with nestin in many areas, yet, sparsely proliferated after the insult. Interestingly, in locally defined zones we found nestin- and glial fibrillary acidic protein-signals clearly separated. In sham-operated animals, nestin could be detected in both neurogenic zones only without co-labeling with glial markers. In conclusion, during the first days after global ischemia, cell death of cornu ammonis, subfield 1-neurons was accompanied by a massive overall proliferation and activation of microglia/macrophages, a reduction of pre-ischemia existing doublecortin-positive precursors in the dentate gyrus and a re-expression of nestin in glial fibrillary acidic protein-positive astrocytes.
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PMID:Increase in proliferation and gliogenesis but decrease of early neurogenesis in the rat forebrain shortly after transient global ischemia. 1621 27

Neurons and oligodendrocyte progenitors are highly sensitive to perinatal hypoxic-ischemic injury. As accumulating evidence suggests that many insults to the human infant occur in utero, and preventing brain damage to infants in utero will prove difficult, there is strong rationale to pursue regenerative strategies to reduce the morbidity associated with developmental brain injuries. The purpose of this study was to determine whether a hypoxic-ischemic insult stimulates the neural stem/progenitor cells in the subventricular zone to generate new neurons and oligodendrocytes. Hypoxia-ischemia was induced using the Vannucci rat model on postnatal day-6 pups. Injections of 5'-bromo-2'-deoxyuridine to label cells undergoing DNA synthesis after hypoxia-ischemia revealed that there is a robust proliferative response within the subventricular zone of the injured hemisphere that continues for at least 1 week after the hypoxic-ischemic episode. Using the neurosphere assay to quantify the number of neural stem/progenitor cells in the subventricular zone, we find that there are twice as many neural stem/progenitor cells in the affected dorsolateral subventricular zone at 1 week of recovery and that these cells generate larger spheres in response to growth factors compared with controls. Precursors from the injured hemisphere generate three times as many neurons in vitro and more than twice as many oligodendroglia compared with controls. Hypoxia-ischemia also increases neurogenesis in vivo. Doublecortin positive cells with migratory profiles were observed streaming from the ipsilateral subventricular zone to the striatum and neocortex, whereas, few doublecortin positive cells were found in the contralateral hemisphere after hypoxia-ischemia. These observations provide evidence that the somatic neural progenitors of the subventricular zone participate in the production of new brain cells lost after hypoxia-ischemia.
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PMID:Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. 1650 31

Thymosin beta (Tbeta) isoforms play an important role in the organization of the cytoskeleton by sequestering G-actin during development of the mammalian brain. In this study, we examined changes in the expression of Tbeta4 and Tbeta15 after transient global ischemia. Tbeta15 mRNA increased gradually in the dentate gyrus (DG) of the hippocampal formation from 3 h after reperfusion and peaked 9 h later. Similarly, a significant increase in Tbeta4 mRNA level was observed in the DG 12 h after reperfusion. Tbeta4 and Tbeta15 proteins were found in different cell types in control brains; Tbeta15 was expressed in a subset of doublecortin (DCX)-positive cells in the DG, whereas Tbeta4-IR was observed in DG neurons and nearby microglial cells. After ischemia, Tbeta15-IR was found in DG neurons and Tbeta4-IR in the reactivated microglial cells. Interestingly, Tbeta15-IR accumulated in the nuclei of CA1 neurons, which are vulnerable to ischemic insults. These results suggest that Tbeta4 and Tbeta15 function in different cellular contexts during ischemia-induced responses.
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PMID:Expression of thymosin beta in the rat brain following transient global ischemia. 1656 8

Adult neurogenesis is modulated by growth factors, physical conditions, and other alterations in the physical microenvironment. We studied the effects of focal ischemia on neurogenesis in the subventricular zone (SVZ), olfactory bulb (OB), and hippocampal dentate gyrus (DG) (known to be persistent neurogenic regions) in the adult non-human primate, the cynomolgus monkey. Three monkeys underwent middle cerebral artery occlusion-induced focal ischemia and were given multiple BrdU injections during the first 2 weeks after ischemia. Twenty-eight days later, the animals were perfused. The number of new neurons (3182 +/- 408/mm3) in the ipsilateral DG of ischemic monkeys was 4.7-fold that in the DG of non-operated monkeys. The number of new neurons (9176 +/- 2295/mm3) in the ipsilateral olfactory bulb of ischemic monkeys was 18.0-fold that in normal olfactory bulb. These observations suggest an increase in the number of new OB neurons, as well as new DG neurons, after focal ischemia in a primate. This substantial increase in new neurons after focal ischemia could result from the enhancement of cell proliferation rather than a change in the rate of cell commitment. Of the three monkeys subjected to ischemia, only one animal possessed a unique progenitor cell type at the most anterior aspect of the ipsilateral SVZ. Within this region, a short migration (approximately 500 microm) of doublecortin-expressing immature neuronal progenitor cells was observed.
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PMID:Increased number of new neurons in the olfactory bulb and hippocampus of adult non-human primates after focal ischemia. 1671 40

Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabinoid agonist R(+)-Win 55212-2 [(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone] or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by approximately 25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by approximately 50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(+)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx- and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.
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PMID:Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis. 1683 55

Neurogenesis persists throughout life under normal and degenerative conditions. The adult subventricular zone (SVZ) generates neural stem cells capable of differentiating to neuroblasts and migrating to the site of injury in response to brain insults. In the present study, we investigated whether estradiol increases neurogenesis in the SVZ in an animal model of stroke to potentially promote the ability of the brain to undergo repair. Ovariectomized C57BL/6J mice were implanted with capsules containing either vehicle or 17beta-estradiol, and 1 week later they underwent experimental ischemia. We utilized double-label immunocytochemistry to identify the phenotype of newborn cells (5-bromo-2'-deoxyuridine-labeled) with various cellular markers; doublecortin and PSA-NCAM as the early neuronal marker, NeuN to identify mature neurons, and glial fibrillary acidic protein to identify astrocytes. We report that low physiological levels of estradiol treatment, which exert no effect in the uninjured state, significantly increase the number of newborn neurons in the SVZ following stroke injury. This effect of estradiol is limited to the dorsal region of the SVZ and is absent from the ventral SVZ. The proliferative actions of estradiol are confined to neuronal precursors and do not influence gliosis. Furthermore, we show that both estrogen receptors alpha and beta play pivotal functional roles, insofar as knocking out either of these receptors blocks the ability of estradiol to increase neurogenesis. These findings clearly demonstrate that estradiol stimulates neurogenesis in the adult SVZ, thus potentially facilitating the brain to remodel and repair after injury.
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PMID:Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. 1718 42

Transient focal ischemia is known to induce proliferation of neural progenitors in adult rodent brain. We presently report that doublecortin positive neuroblasts formed in the subventricular zone (SVZ) and the posterior peri-ventricle region migrate towards the cortical and striatal penumbra after transient middle cerebral artery occlusion (MCAO) in adult rodents. Cultured neural progenitor cells grafted into the non-infarcted area of the ipsilateral cortex migrated preferentially towards the infarct. As chemokines are known to induce cell migration, we investigated if monocyte chemoattractant protein-1 (MCP-1) has a role in post-ischemic neuroblast migration. Transient MCAO induced an increased expression of MCP-1 mRNA in the ipsilateral cortex and striatum. Immunostaining showed that the expression of MCP-1 was localized in the activated microglia and astrocytes present in the ischemic areas between days 1 and 3 of reperfusion. Furthermore, infusion of MCP-1 into the normal striatum induced neuroblast migration to the infusion site. The migrating neuroblasts expressed the MCP-1 receptor CCR2. In knockout mice that lacked either MCP-1 or its receptor CCR2, there was a significant decrease in the number of migrating neuroblasts from the ipsilateral SVZ to the ischemic striatum. These results show that MCP-1 is one of the factors that attract the migration of newly formed neuroblasts from neurogenic regions to the damaged regions of brain after focal ischemia.
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PMID:Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. 1719 Oct 78

Chemokines help to establish cerebral inflammation after ischemia, which comprises a major component of secondary brain injury. The CXCR4 chemokine receptor system induces neural stem cell migration, and hence has been implicated in brain repair. We show that CXCR1 and interleukin-8 also stimulate chemotaxis in murine neural stem cells from the MHP36 cell line. The presence of CXCR1 was confirmed by reverse transcriptase PCR and immunohistochemistry. Interleukin-8 evoked intracellular calcium currents, upregulated doublecortin (a protein expressed by migrating neuroblasts), and elicited positive chemotaxis in vitro. Therefore, effectors of the early innate immune response may also influence brain repair mechanisms.
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PMID:The MHP36 line of murine neural stem cells expresses functional CXCR1 chemokine receptors that initiate chemotaxis in vitro. 1728 63

Ischemic preconditioning (IPC) before subsequent prolonged ischemia is considered an emerging endogenous means of ischemic brain protection. We tested whether IPC induces endogenous neurogenesis in the subventricular zone (SVZ) and angiogenesis in the peri-ischemic area. Middle cerebral artery occlusion was administered to rats by filament insertion for 10 min (IPC) and/or 2 h (prolonged focal ischemia [PFI]). IPC alone increased 5'-bromo-2'-deoxyuridine (BrdU) (+) cells 2.5-fold in the SVZ compared with controls at 7 days. The numbers of BrdU/doublecortin (Dcx) or BrdU/neuronal nuclei (NeuN) double-labeled cells also increased, but extents of BrdU/glial fibrillary acidic protein (GFAP) double-labeling in the SVZ were not different. The IPC+PFI group showed about a 40% reduction in infarct volume. PFI increased BrdU (+) cells in the SVZ, and this was greatly enhanced by IPC treatment. The number of BrdU/Dcx double-labeled cells was strongly increased in ischemic brains administered IPC. Differentiation into mature neurons was also enhanced at 14 and 28 days. In addition, IPC significantly promoted angiogenesis in the ischemic penumbra as indicated by von Willebrand factor (vWF) staining. Our results indicate that IPC enhances neurogenesis in the SVZ even without subsequent PFI, and also enhances neurogenesis and angiogenesis after subsequent PFI. We conclude that IPC confers neuroprotection, and also promotes endogenous neurogenesis and angiogenesis.
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PMID:Ischemic preconditioning enhances neurogenesis in the subventricular zone. 1743 85

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and subgranular zone (SGZ) and increases in the adult after brain injury. In this study, postnatal day 7 rats underwent middle cerebral artery electrocoagulation and transient homolateral common carotid artery occlusion, a lesioning protocol that resulted in ipsilateral (IL) forebrain ischemic injury, leading to a cortical cavity 3 weeks later. The effects of neonatal ischemia on hemispheric damage, cell death, cell proliferation, and neurogenesis were examined 4 hours to 6 weeks later by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunohistochemistry of Ki-67 in proliferating cells and of doublecortin, a microtubule-associated protein expressed only by immature neurons. Neonatal ischemic injury resulted in persistent reduced IL and transient reduced contralateral (CL) hemispheric areas, a consequence of sustained and transient cell death in the IL and CL areas, respectively. Ki-67 immunostaining revealed 3 peaks of newly generated cells in the dorsal SVZ and SGZ in the IL side and also in the CL side at 48 hours and 7 and 28 days after ischemia. Double immunofluorescence revealed that most of the Ki-67-positive cells were astrocytes at 48 hours. Ischemic injury also stimulated SVZ neurogenesis, based on increased doublecortin immunostaining in both SVZs at 7 to 14 days after injury. Doublecortin-positive neurons remained visible around the lesion at 21 days but displayed an immature shape in discrete chains or clusters. Although unilateral ischemic damage was produced, results indicate successful regenerative changes in the CL hemisphere, allowing anatomical recovery.
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PMID:Bilateral changes after neonatal ischemia in the P7 rat brain. 1754 8


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