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

Strategies to provide neuroprotection and to promote regenerative axonal outgrowth in the injured brain are thwarted by the plethora of axon growth inhibitors and the ligand promiscuity of some of their receptors. Especially, new neurons derived from ischemia-stimulated neurogenesis must integrate this multitude of inhibitory molecular cues, generated as a result of cortical damage, into a functional response. More often than not the response is one of growth cone collapse, axonal retraction and neuronal death. Therefore, characterization of the expression of inhibitory molecules in long-term surviving ischemic brains following stroke is important for designing selective therapeutics. Here, we describe a long-term recovery mouse model for cerebral ischemia in which a brief transient occlusion of the middle cerebral artery (30min) was followed by up to 30 days of long-term reperfusion. Significantly decreased grip strength motor function and increased expression of one of the major repulsive guidance cues, Semaphorin 3A (Sema3A) and its receptor Neuropilin1 (NRP1) occurred in brains of these mice. Interestingly, increased Doublecortin (DCX) expression occurred only in the lateral ventricular wall zone, but not in the dentate gyrus granule cell layer on the ischemic side of the brain. Importantly, no DCX positive cells were detected in the infarct core region after 30d ischemic recovery. Collectively, these studies demonstrated the sustained elevation of Sema3A/NRP1 expression in the ischemic territory, which may contribute to the inhibitory microenvironment responsible for preventing new neurons from entering the infarct area. This model will be of use as a platform for testing anti-inhibitory therapies to stroke.
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PMID:Sustained up-regulation of semaphorin 3A, Neuropilin1, and doublecortin expression in ischemic mouse brain during long-term recovery. 1816 77

This study examined whether dietary supplementation can be used to protect against ischemic stroke. Two groups of adult male Sprague-Dawley rats initially received NT-020, a proprietary formulation of blueberry, green tea, Vitamin D3, and carnosine (n = 8), or vehicle (n = 7). Dosing for NT-020 and vehicle consisted of daily oral administration (using a gavage) over a 2-week period. On day 14 following the last drug treatment, all animals underwent the stroke surgery using the transient 1-hour suture occlusion of middle cerebral artery (MCAo). To reveal the functional effects of NT-020, animals were subjected to established behavioral tests just prior to stroke surgery and again on day 14 post-stroke. ANOVA revealed significant treatment effects (p < 0.05), characterized by reductions of 11.8% and 24.4% in motor asymmetry and neurologic dysfunction, respectively, in NT-020-treated stroke animals compared to vehicle-treated stroke animals. Evaluation of cerebral infarction revealed a significant 75% decrement in mean glial scar area in the ischemic striatum of NT-020-treated stroke animals compared to that of vehicle-treated stroke animals (p < 0.0005). Quantitative analysis of subventricular zone's cell proliferative activity revealed at least a one-fold increment in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0005). Similarly, quantitative analysis of BrdU labeling in the ischemic striatal penumbra revealed at least a three-fold increase in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0001). In addition, widespread double labeling of cells with BrdU and doublecortin was detected in NT-020-treated stroke brains (intact side 17% and ischemic side 75%), which was significantly higher than those seen in vehicle-treated stroke brains (intact side 5% and ischemic side 13%) (p < 0.05). In contrast, only a small number of cells in NT-020-treated stroke brains double labeled with BrdU and GFAP (intact side 1% and ischemic side 2%), which was significantly lower than those vehicle-treated stroke brains (intact side 18% and ischemic side 35%) (p < 0.0001). Endogenous neurogenic factors were also significantly upregulated in the ischemic brains of NT-020-treated stroke animals. These data demonstrate the remarkable neuroprotective effects of NT-020 when given prior to stroke, possibly acting via its neurogenic potential.
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PMID:Dietary supplementation exerts neuroprotective effects in ischemic stroke model. 1826 Jul 78

Kallikrein, a serine proteinase, has been identified as an angiogenic growth factor recently. We investigated whether delayed treatment with exogenous kallikrein enhances neurogenesis and angiogenesis after focal cortical infarction in stroke-prone renovascular hypertensive rats. Human tissue kallikrein (1.6 x 10(-2) PNAU/kg) or vehicle was given through a tail vein daily for 6 consecutive days starting 24 h after distal middle cerebral artery occlusion (MCAO). Cell proliferation was examined by using 5'-bromo-2'-deoxyuridine (BrdU, 50 mg/kg). Rats were sacrificed at 3, 7, 14 or 28 d after MCAO, respectively. Treatment with kallikrein significantly increased the number of BrdU(+) cells in the subventricular zone (SVZ) and the peri-infarction region initiating 3 d after MCAO compared with the vehicle group (all p<0.05). Kallikrein significantly increased the number of BrdU(+)/DCX(+) cells and BrdU(+)/nestin(+) cells in the SVZ as well as vascular density in the peri-infarction region compared with the vehicle group (all p<0.05), which increased at 3 d, peaked at 7-14 d after MCAO, and then gradually decreased. Kallikrein markedly increased the number of BrdU(+)/NeuN(+) cells in the peri-infarction region compared with the vehicle group at 14 d and 28 d after MCAO (all p<0.05). The kallikrein group showed better functional improvement after stroke (all p<0.05). Our study demonstrates that delayed administration of kallikrein at 24 h after cortical infarction promotes the SVZ neuroblasts proliferation, migration, and selective differentiation. Moreover, kallikrein enhanced endogenous neurogenesis is associated with angiogenesis, both attributing to functional improvement after stroke. Therefore, kallikrein may have a potential therapeutic perspective on ischemic stroke.
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PMID:Exogenous kallikrein enhances neurogenesis and angiogenesis in the subventricular zone and the peri-infarction region and improves neurological function after focal cortical infarction in hypertensive rats. 1835 82

In response to injury, endogenous precursors in the adult brain can proliferate and generate new neurons, which may have the capacity to replace dysfunctional or dead cells. Although injury-induced neurogenesis has been demonstrated in animal models of stroke, Alzheimer's disease (AD) and Huntington's disease (HD), studies of Parkinson's disease (PD) have produced conflicting results. In this study, we investigated the ability of adult mice to generate new neurons in response to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes selective degeneration of nigrostriatal dopamine neurons. MPTP lesions increased the incorporation of 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU), as well as the number of cells that co-expressed BrdU and the immature neuronal marker doublecortin (DCX), in two neuroproliferative regions-the subgranular zone of the dentate gyrus (DG) and the rostral subventricular zone (SVZ). BrdU-labeled, DCX-expressing cells were not found in the substantia nigra (SN) of MPTP-treated mice, where neuronal cell bodies are destroyed, but were present in increased numbers in the striatum, where SN neurons lost in PD normally project. Fibroblast growth factor-2 (FGF-2), which enhances neurogenesis in a mouse model of HD, also increased the number of BrdU/DCX-immunopositive cells in the SN of MPTP-treated mice. Thus, MPTP-induced brain injury increases striatal neurogenesis and, in combination with FGF-2 treatment, also stimulates neurogenesis in SN.
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PMID:Fibroblast growth factor 2 enhances striatal and nigral neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. 1840 21

Spontaneously hypertensive rats (SHRs) are widely accepted in medical research because this model has been used for studies in neurodegenerative diseases such as vascular dementia and stroke. In the present study, we observed newly generated neuronal precursors using doublecortin (DCX, a marker of neural proliferation and differentiation) in the subgranular zone of the dentate gyrus in SHRs compared to Sprague-Dawley rats (SDRs) at various age stages. DCX immunoreactivity, immunoreactive cell numbers and its protein level in the dentate gyrus of the SHRs were higher than those in the SDRs at postnatal month 1 (PM 1). At PM 8, DCX immunoreactivity, immunoreactive cell numbers and protein levels in both groups were markedly decreased compared to those at PM 1; however, they were higher than those in the SDRs. They were decreased in the both groups with age: DCX immunoreactive cells in the SDRs were few at PM 12. Our results indicate that newly generated neuronal precursors are more abundant in SHRs than in SDRs during their life.
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PMID:Doublecortin-immunoreactive neuronal precursors in the dentate gyrus of spontaneously hypertensive rats at various age stages: comparison with Sprague-Dawley rats. 1846 Aug 32

In this study, we tested the hypothesis that the Angiopoietin 1 (Ang1)/Tie2 pathway mediates simvastatin-induced vascular integrity and migration of neuroblasts after stroke. Rats were subjected to 2 hrs of middle cerebral artery occlusion (MCAo) and treated, starting 1 day after stroke with or without simvastatin (1 mg/kg, daily) for 7 days. Simvastatin treatment significantly decreased blood-brain barrier (BBB) leakage and concomitantly, increased Ang1, Tie2 and Occludin expression in the ischaemic border (IBZ) compared to the MCAo control group. Simvastatin also significantly increased doublecortin (DCX, a marker of migrating neuroblasts) expression in the IBZ compared to control MCAo rats. DCX was highly expressed around vessels. To further investigate the signalling pathway of simvastatin-induced vascular stabilization and angiogenesis, rat brain microvascular endothelial cell (RBMEC) culture was employed. The data show that simvastatin treatment of RBMEC increased Ang1 and Tie2 gene and protein expression and promoted phosphorylated-Tie2 activity. Simvastatin significantly increased endothelial capillary tube formation, an index of angiogenesis, compared to non-treated control. Inhibition of Ang1 or knockdown of Tie2 gene expression in endothelial cells significantly attenuated simvastatin-induced capillary tube formation. In addition, simvastatin significantly increased subventricular zone (SVZ) explant cell migration compared to non-treatment control. Inhibition of Ang1 significantly attenuated simvastatin-induced SVZ cell migration. Simvastatin treatment of stroke increases Ang1/Tie2 expression and thereby reduces BBB leakage and promotes vascular stabilization. Ang1/Tie2 expression induced by simvastatin treatment promotes neuroblast micro-vascular coupling after stroke.
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PMID:Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke. 1854 44

We tested the hypothesis that a nitric oxide donor, DETA-NONOate, up-regulates stromal cell-derived factor-1 (SDF1) and angiopoietin 1 (Ang1) in the ischemic brain and their respective receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hr later DETA-NONOate (0.4 mg/kg) or phosphate-buffered solution was intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis by real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate-induced SVZ migration after stroke, SDF1alpha, Ang1 peptide, a specific antagonist of CXCR4 (AMD3100), and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percentage area of doublecortin (DCX, a marker of migrating neuroblasts)-immunoreactive cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and up-regulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo-alone animals. In vitro, SDF1alpha and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate-induced SVZ cell migration. Our data indicate that treatment of stroke with a nitric oxide donor up-regulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration.
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PMID:Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke. 1871 49

Peripheral stimulation and physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. Using a rodent model of whisker-barrel cortex stroke, we have previously demonstrated that whisker activity promotes angiogenesis in the penumbra of the ischemic barrel cortex. This study explored the potential of increased peripheral activity to promote neurogenesis and neural progenitor migration toward the ischemic barrel cortex. Three days after focal barrel cortex ischemia in adult mice, whiskers were manually stimulated (15 min x 3 times/day) to enhance afferent signals to the ischemic barrel cortex. 5-Bromo-2'-deoxyuridine (BrdU, i.p.) was administered once daily to label newborn cells. At 14 days after stroke, whisker stimulation significantly increased vascular endothelial growth factor and stromal-derived factor-1 expression in the penumbra. The whisker stimulation animals showed increased doublecortin (DCX) positive and DCX/BrdU-positive cells in the ipsilateral corpus of the white matter but no increase in BrdU-positive cells in the subventricular zone, suggesting a selective effect on neuroblast migration. Neurogenesis indicated by neuronal nuclear protein and BrdU double staining was also enhanced by whisker stimulation in the penumbra at 30 days after stroke. Local cerebral blood flow was better recovered in mice that received whisker stimulation. It is suggested that the enriched microenvironment created by specific peripheral stimulation increases regenerative responses in the postischemic brain and may benefit long-term functional recovery from ischemic stroke.
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PMID:Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice. 1877 65

Neurogenesis increases in the adult rodent forebrain subventricular zone (SVZ) after experimental stroke. Newborn neurons migrate to the injured striatum, but few survive long-term and little evidence exists to suggest that they integrate or contribute to functional recovery. One potential strategy to improve stroke recovery is to stimulate neurogenesis and integration of adult-born neurons by using treatments that enhance neurogenesis. We examined the influence of retinoic acid (RA), which stimulates neonatal SVZ and adult hippocampal neurogenesis, and environmental enrichment (EE), which enhances survival of adult-born hippocampal neurons. We hypothesized that the combination of RA and EE would promote survival of adult-generated SVZ-derived neurons and improve functional recovery after stroke. Adult rats underwent middle cerebral artery occlusion, received BrdU on days 5-11 after stroke and were treated with RA/EE, RA alone, EE/vehicle or vehicle alone and were killed 61 days after stroke. Rats underwent repeated MRI and behavioral testing. We found that RA/EE treatment preserved striatal and hemisphere tissue and increased SVZ neurogenesis as demonstrated by Ki67 and doublecortin (DCx) immunolabeling. All treatments influenced the location of BrdU- and DCx-positive cells in the post-stroke striatum. RA/EE increased the number of BrdU/NeuN-positive cells in the injured striatum but did not lead to improvements in behavioral function. These results demonstrate that combined pharmacotherapy and behavioral manipulation enhances post-stroke striatal neurogenesis and decreases infarct volume without promoting detectable functional recovery. Further study of the integration of adult-born neurons in the ischemic striatum is necessary to determine their restorative potential.
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PMID:Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke. 1877 5

Stroke increases neuroblasts in the subventricular zone (SVZ) of the lateral ventricle and these neuroblasts migrate toward the ischemic boundary to replace damaged neurons. Using brain slices from the nonischemic adult rat and transgenic mice that expressed enhanced green fluorescent protein (EGFP) concomitantly with doublecortin (DCX), a marker for migrating neuroblasts, we recorded electrophysiological characteristics while simultaneously analyzing the gene expression in single SVZ cells. We found that SVZ cells expressing the DCX gene from the nonischemic rat had a mean resting membrane potential (RMP) of -30 mV. DCX-EGFP-positive cells in the nonischemic SVZ of the transgenic mouse had a mean RMP of -25+/-7 mV and did not exhibit Na(+) currents, characteristic of immature neurons. However, DCX-EGFP-positive cells in the ischemic SVZ exhibited a hyperpolarized mean RMP of -54+/-18 mV and displayed Na(+) currents, indicative of more mature neurons. Single-cell multiplex RT-PCR analysis revealed that DCX-EGFP-positive cells in the nonischemic SVZ of the transgenic mouse expressed high neural progenitor marker genes, Sox2 and nestin, but not mature neuronal marker genes. In contrast, DCX-EGFP-positive cells in the ischemic SVZ expressed tyrosine hydroxylase, a mature neuronal marker gene. Together, these data indicate that stroke changes gene profiles and the electrophysiology of migrating neuroblasts.
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PMID:Gene profiles and electrophysiology of doublecortin-expressing cells in the subventricular zone after ischemic stroke. 1885 39


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