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

Because neurogenesis persists in the adult mammalian brain and can be regulated by physiological and pathological events, we investigated its possible involvement in the brain's response to focal cerebral ischemia. Ischemia was induced by occlusion of the middle cerebral artery in the rat for 90 min, and proliferating cells were labeled with 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdUrd) over 2-day periods before sacrificing animals 1, 2 or 3 weeks after ischemia. Ischemia increased the incorporation of BrdUrd into cells in two neuroproliferative regions-the subgranular zone of the dentate gyrus and the rostral subventricular zone. Both effects were bilateral, but that in the subgranular zone was more prominent on the ischemic side. Cells labeled with BrdUrd coexpressed the immature neuronal markers doublecortin and proliferating cell nuclear antigen but did not express the more mature cell markers NeuN and Hu, suggesting that they were nascent neurons. These results support a role for ischemia-induced neurogenesis in what may be adaptive processes that contribute to recovery after stroke.
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PMID:Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. 1129

To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.
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PMID:Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke. 1282 74

We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a nitric oxide donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.
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PMID:Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. 1504 60

Stroke increases neurogenesis. The authors investigated whether neural stem cells or progenitor cells in the adult subventricular zone (SVZ) of rats contribute to stroke-induced increase in neurogenesis. After induction of stroke in rats, the numbers of cells immunoreactive to doublecortin, a marker for immature neurons, increased in the ipsilateral SVZ and striatum. Infusion of an antimitotic agent (cytosine-beta-D-arabiofuranoside, Ara-C) onto the ipsilateral cortex eliminated more than 98% of actively proliferating cells in the SVZ and doublecortin-positive cells in the ipsilateral striatum. However, doublecortin-positive cells rapidly replenished after antimitotic agent depletion of actively proliferating cells. Depleting the numbers of actively proliferating cells in vivo had no effect on the numbers of neurospheres formed in vitro, yet the numbers of neurospheres derived from stroke rats significantly (P<0.05) increased. Neurospheres derived from stroke rats self-renewed and differentiated into neurons and glia. In addition, doublecortin-positive cells generated in the SVZ migrated in a chainlike structure toward ischemic striatum. These findings indicate that in the adult stroke brain, increases in recruitment of neural stem cells contribute to stroke-induced neurogenesis, and that newly generated neurons migrate from the SVZ to the ischemic striatum.
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PMID:Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. 1508 13

We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances ( approximately 1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker beta-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.
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PMID:Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. 1528 May 35

Human bone marrow stromal cells (hMSCs) enhance neurological recovery after stroke in rodents, possibly via induction of growth factors. We therefore elected to test the effects of hMSC treatment on insulin-like growth factor 1 (IGF-1), which plays an important role in growth, development, neuroprotection and repair in the adult. Rats (n=57) were subjected to permanent middle cerebral artery occlusion (MCAo) and injected intravenously with 3 x 10(6) hMSCs or phosphate-buffered saline (PBS) at 1 day after MCAo. Functional outcome was measured after MCAo using a modified Neurological Severity Score (mNSS). Gene expression of IGF-1 and IGF-1 receptor (IGF-1R) in the ischemic brain tissue were measured at 2 and 7 days after MCAo using reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry was performed to measure the expression of bromodeoxyuridine (BrdU), doublecortin (DCX), IGF-1 and IGF-1R at 7, 14 and 30 days after MCAo. Treatment of MCAo with hMSCs significantly improved functional recovery from 14 to 30 days. MAB1281-labeled hMSCs entered the ischemic brain and increased time-dependently. hMSC treatment significantly increased IGF-1 mRNA and BrdU(+), DCX(+), IGF-1(+) and IGF-1R(+) cells compared to PBS-treated rats (p<0.05). The percentage of BrdU(+) or DCX(+) cells colocalized with IGF-1 increased in the hMSC-treated rats compared to the PBS-treated rats (p<0.05). IGF-1 and IGF-1R may contribute to improved functional recovery and increased neurogenesis after treatment of stroke with hMSCs.
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PMID:Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. 1556 34

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

Nitric oxide (NO) influences infarct size after focal cerebral ischemia and also regulates neurogenesis in the adult brain. These observations suggest that therapeutic approaches to stroke that target NO signaling may provide neuroprotection and also enhance brain repair through cell replacement. However, ischemic injury and neurogenesis are both affected differently depending on which isoform of NO synthase is the source of NO. In addition, ischemia itself stimulates neurogenesis, and ischemia-induced neurogenesis may be regulated differently than neurogenesis in nonischemic brain. To determine how neuronal NO synthase affects ischemia-induced neurogenesis, transient focal cerebral ischemia was produced in wild-type mice and in knockout mice lacking neuronal NO synthase, and BrdU incorporation and doublecortin immunoreactivity were measured in the principal neuroproliferative regions of the adult brain. Knockout of neuronal NO synthase reduced infarct size and increased both basal and ischemia-induced neurogenesis, suggesting that NO from this source is an inhibitory regulator of neurogenesis in the ischemic brain. 7-Nitroindazole, an NO synthase inhibitor that preferentially affects the neuronal isoform, also increased neurogenesis in rats when administered by the intracerebroventricular route. Selective inhibition of neuronal NO synthase may have the potential to both reduce infarct size and enhance neurogenesis in stroke.
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PMID:Neuronal nitric oxide synthase and ischemia-induced neurogenesis. 1568 58

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

Experimental stroke increases cell proliferation and neurogenesis in the subventricular zone (SVZ) and in the dentate gyrus subgranular zone (SGZ) in the adult mammalian brain. This study examined the effects of postischemic voluntary exercise (running wheel) and environmental enrichment on the SVZ and SGZ 1 week after focal cortical ischemia in adult spontaneously hypertensive rats. Immunohistochemical labeling was performed for incorporation of specific cell markers such as Ki67 and 5-bromodeoxyuridine (proliferating and newborn cells), terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling (apoptotic cells), Sox-2 and glial fibrillary acidic protein (neural stem and progenitor cells), polysialylated neural cell adhesion molecule and doublecortin (neuroblasts). Postischemic exercise and environmental enrichment differentially modulated SVZ cell genesis but lacked effects on the SGZ. Lesion-induced proliferation of neural stem/progenitor cells and neuronal precursors was attenuated in stroke runners without any effects on apoptosis or neuronal migration in the forebrain. Running activity did not affect the SVZ in intact rats. In contrast to postischemic wheel running, postischemic environmental enrichment did not have attenuating effects on the ipsilateral SVZ and increased proliferating putative neural stem cells and neuronal precursors contralaterally. A significant functional improvement, assessed using a rotating pole, was observed only in the postischemically enriched group and was likely due to other types of plasticity than neuronal replacement at this early time point. It may be concluded that in contrast to enriched environment, exercise during the first postischemic week might be detrimental for regenerative processes initiated in the SVZ after stroke.
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PMID:Postischemic exercise attenuates whereas enriched environment has certain enhancing effects on lesion-induced subventricular zone activation in the adult rat. 1593 98


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