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

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients. More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized. Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation. In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.
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PMID:CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. 1214 5

Astrocytes react to all noxae which damage neurons. Their reactions include degeneration, hypertrophy, hyperplasia and fibre formation. Growth factors inducing proliferation and differentiation of both neurons and astrocytes in culture play a pivotal role in the dynamic flow of signaling molecules between neurons and astroglia. Estrogens as well influence astroglia and are neuroprotectants. This study has investigated the interactions between growth factors and estrogens on DNA labeling and cytoskeletal protein [glial fibrillary acidic protein (GFAP) and vimentin] expression in 22 DIV astrocyte cultures treated for 24 or 36 h under different experimental conditions. Contemporary addition of 17-beta-estradiol (E2) with two or three growth factors for 24 h, significantly stimulated methyl-[3H]thymidine incorporation into DNA from 22 days in vitro (DIV) astrocyte cultures. This effect reached a peak when E2 was co-added with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin. In astrocyte cultures treated for 36 h with E2 and EGF + insulin or bFGF + insulin added in the last 12 h, DNA labeling was remarkably increased. The parallel cyclin Dl expression positively correlated with ERK2 activation. Western blot analysis for cytoskeletal proteins showed also changes of both GFAP and vimentin expression. The above data suggest the occurrence of a scheduled interaction between "competence" or "progression" growth factors and estrogens on DNA labeling and cytoskeletal protein expression during astroglial cell proliferation and differentiation in culture. A better understanding of the mechanisms of these interactions may contribute to develop strategies for controlling astroglial reaction in cerebrovascular disease including stroke and hypertensive brain damage.
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PMID:Effect of growth factors on DNA labeling and cytoskeletal protein expression in 17-beta-estradiol and basic fibroblast growth factor pre-treated astrocyte cultures. 1245 Feb 49

Previously, we have demonstrated that mRNA expression of endothelin-1 (ET-1), a potent vasoconstrictor, is induced in astrocytes and endothelial cells after ischemic conditions, suggesting that both of these cells synthesize ET-1 under this stress condition. Furthermore, ET-1 protected primary cultured astrocytes from ischemic stress. In order to further investigate the role of endothelial ET-1 in cerebral ischemic injury, transgenic mouse lines (TET) with a transgene that included ET cDNA with SV40 polyA under tyrosine kinase with immunoglobulin and epidermal growth factor homology domain (Tie-1) promoter were used. TET mouse lines were further characterized for ET-1 over-expression in the brain. The reverse transcription-polymerase chain reaction (RT-PCR) analysis using the primers specific for transgene ET-1 showed that transgene ET-1 is only expressed in the brain from TET mice. Total expression of ET- 1 mRNA was also increased in the transgenic brain compared with the non-transgenic brain by semi-quantitative RT-PCR. In situ hybridization and immunocytochemical analyses showed that the increased ET-1 mRNA and peptide expressions were detected in endothelial cells of cerebral vessels of TET mice. Under normal conditions, the TET mice that have a slightly increased blood pressure compared with that of non-transgenic mice showed no gross morphological abnormalities in the brain. However, after transient middle cerebral artery occlusion, TET mice showed a more severe neurological deficit, and larger infarct size and volume, suggesting that over-expressing ET-1 in endothelial cells is deleterious to neuronal survival under ischemic conditions. Our present TET model will serve as an ideal model for studying the role of endothelial ET- 1 in the pathogenesis of ischemic stroke.
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PMID:Endothelial cell-specific over-expression of endothelin-1 leads to more severe cerebral damage following transient middle cerebral artery occlusion. 1583 4

Mutations in the NOTCH3 gene trigger adult-onset stroke and vascular dementia in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). All CADASIL mutations described to date affect the epidermal growth factor-like (EGF-like) repeats located in the extracellular domain of the Notch3 receptor. These domains are also the target of sequential complex O-linked glycosylation mediated by protein O-fucosyltransferase 1 and Fringe. We investigated whether O-fucosylation or Fringe-mediated elongation of O-fucose on Notch3 is impaired by CADASIL mutations. Biochemical studies of a Notch3 fragment containing the first five EGF-like repeats of Notch3, including the mutational hot spot, showed that CADASIL mutations do not affect the addition of O-fucose but do impair carbohydrate chain elongation by Fringe. CADASIL changes also induced aberrant homodimerization of mutant Notch3 fragments and heterodimerization of mutant Notch3 with Lunatic Fringe itself. Together, these data suggest that Fringe plays a role in CADASIL pathophysiology.
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PMID:CADASIL mutations impair Notch3 glycosylation by Fringe. 1585 53

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP.
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PMID:Neuregulin 1-Beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol. 1682 72

Recent studies suggest that proliferation in the adult forebrain subventricular zone increases in response to a forebrain stroke and intraventricular infusions of growth factors enhance this response. The potential for growth factor infusions to regenerate the damaged motor cortex and promote recovery of motor function after stroke has not been examined. Here, we report that intraventricular infusions of epidermal growth factor and erythropoietin together, but not individually, promote substantial regeneration of the damaged cerebral cortex and reverse impairments in spontaneous and skilled motor tasks, in a rat model of stroke. Cortical regeneration and functional recovery occurred even when growth factor administration was delayed for up to 7 days after the stroke-induced lesion. Cell tracking demonstrated the contribution of neural precursors originating in the forebrain subventricular zone to the regenerated cortex. Strikingly, removal of the regenerated cortical tissue reversed the growth factor-induced functional recovery. These findings reveal that specific combinations of growth factors can mobilize endogenous adult neural stem cells to promote cortical tissue re-growth and functional recovery after stroke.
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PMID:Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. 1698 5

The membrane-anchored metalloproteinase tumor necrosis factor-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase [ADAM] 17) is key in proteolytic ectodomain shedding of several membrane-bound growth factors, cytokines and receptors. The expression and activity of ADAM17 increases under some pathological conditions including stroke, and promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis. Hypoxia initiates cellular invasive processes that occur under both physiological and pathological conditions such as invasion and metastasis of some tumors. In the present study, we sought to elucidate whether ADAM17 contributes to brain tumor invasion. To this end, we examined the role of ADAM17 in the invasiveness of two different brain tumor cell lines, 9L rat gliosarcoma and U87 human glioma, under normoxic and hypoxic conditions. Additionally, we tested the effects of ADAM17 suppression on in vitro tumor cell invasion by means of ADAM17 proteolytic inhibitors and specific small interfering RNA. We found that tumor cells upregulated ADAM17 expression under hypoxia, and that ADAM17 activity correlated with increased tumor cell invasion. Conversely, suppression of ADAM17 proteolysis decreased invasiveness induced by hypoxia in 9L and U87 cells. Furthermore, the contribution of ADAM17 to tumor invasion was independent of matrix metalloproteinase (MMP)-2 and MMP-9 activity. ADAM17 was also found to activate the epidermal growth factor/phosphoinositide-3 kinase/serine/threonine kinase signal transduction pathway. Our data suggest that hypoxia-induced ADAM17 contributes to glioma cell invasiveness through activation of the EGFR signal pathway.
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PMID:Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness. 1735 61

Endocannabinoids are lipid signaling mediators that exert an important neuromodulatory role and confer neuroprotection in several types of brain injury. Excitotoxicity and stroke can induce neural progenitor (NP) proliferation and differentiation as an attempt of neuroregeneration after damage. Here we investigated the mechanism of hippocampal progenitor cell engagement upon excitotoxicity induced by kainic acid administration and the putative involvement of the CB1 cannabinoid receptor in this process. Adult NPs express kainate receptors that mediate proliferation and neurosphere generation in vitro via CB1 cannabinoid receptors. Similarly, in vivo studies showed that excitotoxicity-induced hippocampal NPs proliferation and neurogenesis are abrogated in CB1-deficient mice and in wild-type mice administered with the selective CB1 antagonist rimonabant (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide; SR141716). Kainate stimulation increased basic fibroblast growth factor (bFGF) expression in cultured NPs in a CB1-dependent manner as this response was prevented by rimonabant and mimicked by endocannabinoids. Likewise, in vivo analyses showed that increased hippocampal expression of bFGF, as well as of brain-derived neurotrophic factor and epidermal growth factor, occurs upon excitotoxicity and that CB1 receptor ablation prevents this induction. Moreover, excitotoxicity increased the number of CB1+ bFGF+ cells, and this up-regulation preceded NP proliferation. In summary, our results show the involvement of the CB1 cannabinoid receptor in NP proliferation and neurogenesis induced by excitotoxic injury and support a role for bFGF signaling in this process.
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PMID:The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. 1755 69

Treatment of rodents after stroke with bone marrow stromal cells (BMSCs) improves functional outcome. However, the mechanisms underlying this benefit have not been ascertained. This study focused on the contribution of neurotrophic and growth factors produced by BMSCs to therapeutic benefit. Rats were subjected to middle cerebral artery occlusion and the ischemic brain extract supernatant was collected to prepare the conditioned medium. The counterpart normal brain extract from non-ischemic rats was employed as the experimental control. Using microarray assay, we measured the changes of the neurotrophin associated gene expression profile in BMSCs cultured in different media. Furthermore, real-time RT-PCR and fluorescent immunocytochemistry were utilized to validate the gene changes. The morphology of BMSCs, cultured in the ischemic brain-conditioned medium for 12 h, was dramatically altered from a polygonal and flat appearance to a fibroblast-like long and thin cell appearance, compared to those in the normal brain-conditioned medium and the serum replacement medium. Forty-four neurotrophin-associated genes in BMSCs were identified by microarray assay under all three culture media. Twelve out of the 44 genes (7 neurotrophic and growth factor genes, 5 receptor genes) increased in BMSCs cultured in the ischemic brain-conditioned medium compared to the normal brain-conditioned medium. Real time RT-PCR and immunocytochemistry validated that the ischemic brain-conditioned medium significantly increased 6/7 neurotrophic and growth factor genes, compared with the normal brain-conditioned medium. These six genes consisted of fibroblast growth factor 2, insulin-like growth factor 1, vascular endothelial growth factor A, nerve growth factor beta, brain-derived neurotrophic factor and epidermal growth factor. Our results indicate that transplanted BMSCs may work as 'small molecular factories' by secreting neurotrophins, growth factors and other supportive substances after stroke, which may produce therapeutic benefits in the ischemic brain.
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PMID:Neurotrophic and growth factor gene expression profiling of mouse bone marrow stromal cells induced by ischemic brain extracts. 1789 89

Hypertonia, which is characterized by stiff gait, abnormal posture, jerky movements, and tremor, is associated with a number of neurological disorders, including cerebral palsy, dystonia, Parkinson's disease, stroke, and spinal cord injury. Recently, a spontaneous mutation in the gene encoding trafficking protein, kinesin-binding 1 (Trak1), was identified as the genetic defect that causes hypertonia in mice. The subcellular localization and biological function of Trak1 remain unclear. Here we report that Trak1 interacts with hepatocyte-growth-factor-regulated tyrosine kinase substrate (Hrs), an essential component of the endosomal sorting and trafficking machinery. Double-label immunofluorescence confocal studies show that the endogenous Trak1 protein partially colocalizes with Hrs on early endosomes. Like Hrs, both overexpression and small-interfering-RNA-mediated knockdown of Trak1 inhibit degradation of internalized epidermal growth factor receptors through a block in endosome-to-lysosome trafficking. Our findings support a role for Trak1 in the regulation of Hrs-mediated endosomal sorting and have important implications for understanding hypertonia associated with neurological disorders.
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PMID:Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking. 1867 23


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