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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transgenic technique allows specific genetic alterations to be made in all cells of an animal and this has greatly improved our understanding of how the embryonic and adult central nervous system (CNS) develop. The CNS originates from the neuroectoderm in the neural plate on the dorsal side of the embryo and after closure of the neural tube the cells of the neuroepithelium, i.e. the CNS stem cells, transiently proliferate to generate neurons and glial cells. Here we review our attempts to gain insights into the control of CNS development. We have identified a gene, nestin, which is predominantly expressed in embryonic and adult CNS stem cells. In addition to its normal expression in the CNS stem cells, nestin is reexpressed in CNS tumors and in the adult spinal cord and brain after CNS injury. By using the lacZ reporter gene assay in transgenic mice, we have identified regulatory regions (enhancer) in the nestin gene required for expression in embryonic CNS stem cells and in the adult spinal cord after injury. In a second project, we have cloned and characterized the Notch gene family (the Notch 1, 2 and 3 genes) in mouse and man. These genes encode trans-membrane receptors, which appear to be key regulatory molecules for proliferation and differentiation both in the developing CNS and in other tissues. Expression of an activated form of the Notch 3 receptor from the nestin promoter in transgenic mice leads to a lethal, exencephaly-like phenotype in the embryo, probably as a result of excess proliferation of the CNS stem cells. The recent finding that the Notch 3 gene is the genetic cause for familial stroke is discussed in the context of current models for Notch function.
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PMID:Transgenic analysis of central nervous system development and regeneration. 924 56

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

Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.
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PMID:[Neuroprotective actions of lithium]. 1270 Dec 14

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

Here, we investigate the effects of endothelial nitric oxide synthase (eNOS) on angiogenesis, neurogenesis, neurotrophic factor expression, and neurological functional outcome after stroke. Wild-type and eNOS knock-out (eNOS-/-) mice were subjected to permanent occlusion of the right middle cerebral artery. eNOS-/- mice exhibited more severe neurological functional deficit after stroke than wild-type mice. Decreased subventricular zone (SVZ) progenitor cell proliferation and migration, measured using bromodeoxyuridine, Ki-67, nestin, and doublecortin immunostaining in the ischemic brain, and decreased angiogenesis, as demonstrated by reduced endothelial cell proliferation, vessel perimeter, and vascular density in the ischemic border, were evident in eNOS-/- mice compared with wild-type mice. eNOS-deficient mice also exhibited a reduced response to vascular endothelial growth factor (VEGF)-induced angiogenesis in a corneal assay. ELISAs showed that eNOS-/- mice have decreased brain-derived neurotrophic factor (BDNF) expression but not VEGF and basic fibroblast growth factor in the ischemic brain compared with wild-type mice. In addition, cultured SVZ neurosphere formation, proliferation, telomerase activity, and neurite outgrowth but not cell viability from eNOS-/- mice were significantly reduced compared with wild-type mice. BDNF treatment of SVZ cells derived from eNOS-/- mice restored the decreased neurosphere formation, proliferation, neurite outgrowth, and telomerase activity in cultured eNOS(-/-) SVZ neurospheres. SVZ explant cell migration also was significantly decreased in eNOS-/- mice compared with wild-type mice. These data indicate that eNOS is not only a downstream mediator for VEGF and angiogenesis but also regulates BDNF expression in the ischemic brain and influences progenitor cell proliferation, neuronal migration, and neurite outgrowth and affects functional recovery after stroke.
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PMID:Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. 1574 63

We induced neural cells by treating cynomolgus monkey embryonic stem (ES) cells with retinoic acid. The treated cells mainly expressed betaIIItubulin. They further differentiated into neurons expressing neurofilament middle chain (NFM) in elongated axons. Half of the cells differentiated into Islet1+ motoneurons in vitro. The monkey ES-derived neural cells were transplanted to hemiplegic mice with experimental brain injury mimicking stroke. The neural cells that had grafted into periventricular area of the mice distributed extensively over the injured cortex. Some of the transplanted cells expressed the neural stem/progenitor marker nestin 2 days after transplantation. The cells expressed markers characteristic of mature motoneurons 28 days after transplantation. Mice with the neural cell graft gradually recovered motor function, whereas control animals remained hemiplegic. This is the first demonstration that neural cells derived from nonhuman primate ES cells have the ability to restore motor function in an animal model of brain injury.
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PMID:Transplantation of neural cells derived from retinoic acid-treated cynomolgus monkey embryonic stem cells successfully improved motor function of hemiplegic mice with experimental brain injury. 1613 65

Previous reports have indicated that the expression of bone morphogenetic protein-7 (BMP7) is enhanced after ischemic injury in brain. This upregulation may induce endogenous neurorepair in the ischemic brain. The purpose of this study was to examine neuroregenerative effects of BMP7 after ischemia-reperfusion injury. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. Right middle cerebral artery (MCA) was transiently ligated with 10-O suture for 1 h. One day after MCA occlusion, vehicle or BMP7 was infused to the contralateral cerebral ventricle. To identify possible neurogenesis, bromodeoxyurindine (BrdU) was systemically injected on the fourth and fifth days after MCA occlusion. Animals treated with BMP7 showed a rapid correction of body asymmetry and neurological deficits, suggesting BMP7 facilitates recovery after stroke. Animals were sacrificed at 1 month after stroke and brains were analyzed using immunohistological techniques. BMP7 treatment enhanced immunoreactivity of BrdU in the subventricular zone, lesioned cortex, and corpus callosum. These BrdU-positive cells co-labeled with nestin and NeuN. Our behavioral and anatomical data suggest that BMP7 promotes neuroregeneration in stroke animals, possibly through the proliferation of new neuronal precursors after ischemia.
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PMID:Neuroregenerative effects of BMP7 after stroke in rats. 1623 21

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.
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PMID:Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. 1642 25

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

Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.
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PMID:Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. 1709 Jun 84


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