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

Exogenous erythropoietin (EPO) is a potent neurotrophic factor in vivo, protective against neuronal death in animal models of brain ischemia and human stroke. To date, reports on the distribution of EPO receptor in brain suggest that it is expressed mostly on capillaries. This receptor pattern suggests an indirect effect of EPO on neurons. In these studies, we show that EPO receptor is abundantly expressed on adult dopaminergic neurons, suggesting a direct effect of EPO on neurons. Furthermore, we show that EPO mediates the classic neurotrophic effects of proliferation, differentiation and maintenance in a dopaminergic cell line. The biology of therapeutically administered EPO in brain is a function of its receptor distribution, and the neuronal expression of EPO receptor on adult CNS neurons is consistent with EPO's potent neurotrophic function in vivo.
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PMID:Erythropoietin receptor is expressed on adult rat dopaminergic neurons and erythropoietin is neurotrophic in cultured dopaminergic neuroblasts. 1505 Jul 26

More than 8,000 researchers, clinicians and exhibitors from around the world gathered in San Francisco for the American Academy of Neurology 56th Annual Meeting, April 24 to May 1, 2004. Of the 1,300 studies at the conference, researchers presented more than 200 abstracts each on multiple sclerosis, stroke and dementia, 145 on epilepsy, 159 on Parkinson's disease, 132 on pain and about 50 each on tremor and dystonia. The use of brain imaging technology also figured strongly in the program, with 300 abstracts that mentioned magnetic resonance imaging and 50 that included positron emission tomography. Highlights included promising Parkinson's disease studies involving gene therapy and treatments using glial-cell-derived neurotrophic factor, but also new evidence of cardiac valve regurgitation associated with pergolide. Other highlights included studies on neural repair, new guidelines for the treatment of epilepsy and important studies comparing the thrombin inhibitor ximelagatran to warfarin for the prevention of stroke.
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PMID:New developments in the treatment of neurological diseases. 1533 92

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

Sympathetic hyper-innervation and increased levels of nerve growth factor (NGF), an essential neurotrophic factor for sympathetic neurons, have been observed in the vascular tissues of spontaneously hypertensive rats (SHRs). Such observations have suggested that the pathogenesis of hypertension might involve a qualitative or quantitative abnormality in the NGF protein, resulting from a significant mutation in the gene's promoter or coding region. In the present study, we analyzed the nucleotide sequences of the cis-element of the NGF gene in SHRs, stroke-prone SHRs (SHRSPs), and normotensive Wistar-Kyoto (WKY) rats. The present analyses revealed some differences in the 3-kb promoter region, coding exon, and 3' untranslated region (3'UTR) for the NGF gene among those strains. However, the observed differences did not lead to changes in promoter activity or to amino acid substitution; nor did they represent a link between the 3'UTR mutation of SHRSPs and elevated blood pressure in an F2 generation produced by crossbreeding SHRSPs with WKY rats. These results suggest that the NGF gene locus is not involved in hypertension in SHR/ SHRSP strains. The present study also revealed two differences between SHRs and WKY rats, as found in cultured vascular smooth muscle cells and in mRNA prepared from each strain. First, SHRs had higher expression levels of c-fos and c-jun genes, which encode the component of the AP-1 transcription factor that activates NGF gene transcription. Second, NGF mRNAs prepared from SHRs had a longer 3'UTR than those prepared from WKY rats. Although it remains to be determined whether these events play a role in the hypertension of SHR/SHRSP strains, the present results emphasize the importance of actively searching for aberrant trans-acting factor(s) leading to the enhanced expression of the NGF gene and NGF protein in SHR/SHRSP strains.
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PMID:No involvement of the nerve growth factor gene locus in hypertension in spontaneously hypertensive rats. 1602 43

G-CSF (Granulocyte-colony stimulating factor) is a hematopoietic growth factor that has been known for 20 years, and has been named for its role in the proliferation and differentiation of cells of the myeloic lineage. We have uncovered a novel spectrum of activities of G-CSF in the central nervous system. G-CSF and its receptor are expressed by neurons in many brain regions, and are upregulated upon experimental stroke. In neurons, G-CSF acts anti-apoptotically by activating several protective pathways. In vivo, G-CSF decreases infarct volumes in acute stroke models in rodents. Moreover, G-CSF stimulates neuronal differentiation of adult neural stem cells in the brain, and improves long-term recovery in more chronic stroke models. Thus, G-CSF is a novel neurotrophic factor, and a highly attractive candidate for the treatment of neurodegenerative conditions. Here we discuss this new property of G-CSF in contrast to its known functions in the hematopoietic system, summarize data from other groups on G-CSF's actions in cerebral ischemia, compare G-CSF to Erythropoietin (EPO) in the CNS, and highlight clinical implications.
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PMID:A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. 1625 90

Although stem cell-based treatments for stroke and other neurodegenerative diseases have advanced rapidly, there are still few clinical treatments available. In this study, rats receiving intracerebral peripheral blood hematopoietic stem cell (CD34+) (PBSC) transplantation showed much more improvement in neurological function after chronic cerebral ischemia in comparison with vehicle-treated control rats. Using laser-scanning confocal microscopy, implanted PBSCs were seen to differentiate into glial cells [GFAP+ (glial fibrillary acidic protein-positive)], neurons [Nestin+, MAP-2+ (microtubule-associated protein 2-positive), Neu-N+ (neuronal nuclear antigen-positive)], and vascular endothelial cells [vWF+ (von Willebrand factor-positive)], thereby enhancing neuroplastic effects in the ischemic brain. Cortical neuronal activity, as evaluated by 1H-MRS (proton magnetic resonance spectroscopy), also increased considerably in PBSC-treated rats compared with a vehicle-treated control group. In addition, PBSC implantation promoted the formation of new vessels, thereby increasing the local cortical blood flow in the ischemic hemisphere. These observations may be explained by the involvement of stem cell-derived macrophage/microglial cells, and beta1 integrin expression, which might enhance this angiogenic architecture over the ischemic brain. Furthermore, quantitative reverse transcription-PCR analysis showed significantly increased modulation of neurotrophic factor expression in the ischemic hemisphere of the PBSC-transplanted rats compared with vehicle-treated control rats. Thus, intracerebral PBSC transplantation might have potential as a therapeutic strategy for treating cerebrovascular diseases.
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PMID:Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. 1657 51

Astrocytes are thought to be critical to neurons' surviving damage caused by ischemic stroke or other injury. Plasminogen activator inhibitor-1 is one of the active soluble factors released by astrocytes and regulates plasminogen activator-plasmin proteolytic sequence in the CNS as a serpin. In this study, we show that plasminogen activator inhibitor-1 can promote neurite outgrowth and survival of rat pheochromocytoma cells in serum-deprived conditions, and that this neuroprotective activity is correlated with enhanced activation of both extracellular signal-regulated kinases following a direct phosphorylation of nerve growth factor receptor, Trk A, and of c-Jun. Our results suggest that plasminogen activator inhibitor-1 can act as a neurotrophic factor, protecting neurons from serum deprivation-induced neuron death not only by compensating for nerve growth factor functions, but also by activating the c-Jun/activating protein-1 pathway.
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PMID:Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. 1667 72

Possible strategies for treating ischaemic stroke include: (i) neuroprotection (preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischaemia), and (ii) neurosupplementation (the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischaemia). In this paper, we review our recent progress in development of these distinct new strategies for treatment of damaged brain following a stroke. Firstly, we investigated the role of endogenous IL-6 (interleukin-6), which is one of the cytokines drastically induced by ischaemic stimuli, by administering IL-6RA (anti-IL-6 receptor monoclonal antibody) to mice. We found that endogenous IL-6 plays a critical role in neuroprotection and that its role may be mediated by STAT3 (signal transducer and activator of transcription-3) activation. Secondly, we studied the endogenous sources of the newly born neurons in the ischaemic striatum by region- and cell-type-specific cell labelling techniques. The results revealed that the SVZ (subventricular zone) is the principal source of the neuronal progenitors that migrate laterally towards the infarcted regions, and differentiate into newly born neurons. Finally, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is an appropriate poly-porous structure releasing bioactive substances such as neurotrophic factor. This bio-affinitive scaffold is able to give an appropriate environment for newly born neurons. In future, we will combine these strategies to develop more effective therapies for treatment of strokes.
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PMID:Neuroprotection and neurosupplementation in ischaemic brain. 1707 9

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine responsible for the proliferation, differentiation, and maturation of cells of the myeloid lineage, which was cloned more than 20 years ago. Here we uncovered a novel function of GM-CSF in the central nervous system (CNS). We identified the GM-CSF alpha-receptor as an upregulated gene in a screen for ischemia-induced genes in the cortex. This receptor is broadly expressed on neurons throughout the brain together with its ligand and induced by ischemic insults. In primary cortical neurons and human neuroblastoma cells, GM-CSF counteracts programmed cell death and induces BCL-2 and BCL-Xl expression in a dose- and time-dependent manner. Of the signaling pathways studied, GM-CSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity. Intravenously given GM-CSF passes the blood-brain barrier, and decreases infarct damage in two different experimental stroke models (middle cerebral artery occlusion (MCAO), and combined common carotid/distal MCA occlusion) concomitant with induction of BCL-Xl expression. Thus, GM-CSF acts as a neuroprotective protein in the CNS. This finding is remarkably reminiscent of the recently discovered functionality of two other hematopoietic factors, erythropoietin and granulocyte colony-stimulating factor in the CNS. The identification of a third hematopoietic factor acting as a neurotrophic factor in the CNS suggests a common principle in the functional evolution of these factors. Clinically, GM-CSF now broadens the repertoire of hematopoietic factors available as novel drug candidates for stroke and neurodegenerative diseases.
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PMID:A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). 1745 67

Ammonium trichloro(dioxoethylene-0,0') tellurate (AS101) is a non-toxic organotellurium compound with pleiotropic activities. It was recently shown to induce production of the neurotrophic factor glial cell line-derived neurotrophic factor and to rescue neuronal-like PC-12 cells from neurotrophic factor deprivation-induced apoptosis. In this study, we show that AS101 improves functional outcome and reduces brain damage in a mouse model of focal ischemic stroke. Both pre-stroke and post-stroke intraperitoneal treatments with AS101 reduced infarct size and edema and improved the neurological function of the animals. AS101 treatments reduced both apoptotic and inflammatory caspase activities, and also inhibited protein tyrosine nitration suggesting that AS101 suppresses oxidative stress. Studies of cultured neurons showed that AS101 confers protection against apoptosis induced by either glucose deprivation or the lipid peroxidation product 4-hydroxynonenal. Moreover, AS101 treatment reduced glutamate-induced intracellular calcium elevation, a major contributor to neuronal death in stroke. As AS101 has an excellent safety profile in humans, our pre-clinical data suggest a potential therapeutic benefit of AS101 in patients suffering from stroke and other neurodegenerative conditions.
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PMID:The organotellurium compound ammonium trichloro(dioxoethylene-0,0') tellurate enhances neuronal survival and improves functional outcome in an ischemic stroke model in mice. 1754 9


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