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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of ischemic brain injury in cell culture, animal models, and humans have revealed inter- and intra-cellular signaling pathways that increase resistance to cell degeneration and death. Brain injury induces expression of many different growth factors and cytokines which can protect neurons against insults relevant to the pathogenesis of ischemic brain injury including excitotoxicity, hypoxia, hypoglycemia, acidosis, and pro-oxidants. Neuroprotective signal transduction pathways elicit changes that promote the maintenance of cellular ion homeostasis and/or suppress the accumulation of free radicals. For example: basic fibroblast growth factor suppresses expression of a glutamate receptor protein and induces antioxidant enzymes; tumor necrosis factor induces expression of a Ca(2+)-binding protein and Mn-superoxide dismutase; and secreted forms of beta-amyloid precursor protein hyperpolarize neurons by activating K+ channels. Transcriptional regulation involves activation of tyrosine phosphorylation cascades and NFkB. Interestingly, similar neuroprotective pathways can be activated by moderate levels of cell "stress" such as that induced by glutamate in cell culture or a brief period of cerebral ischemia in vivo. Novel rapid and delayed intracellular neuroprotective signaling mechanisms are being revealed, such as the regulation of Ca2+ influx by actin filaments and the induction of genes by Ca2+ and radicals. New therapeutic approaches arising from this research include low molecular weight lipophilic compounds that activate neurotrophic factor signaling pathways and agents that selectively depolymerize actin.
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PMID:Neuroprotective signal transduction: relevance to stroke. 906 43

Hepatocyte growth factor (HGF) was originally discovered as a powerful mitogen for hepatocytes. HGF also has been reported to function as a neurotrophic factor as well as an angiogenetic factor. The present study examined the neuroprotective effect of HGF against transient focal cerebral ischemia in rats, in which an anti-apoptotic and an angiogenetic effect of HGF was assumed to contribute to the reduction of the infarct volume. The intraventricular administration of human recombinant HGF prevented neuronal death after 120 min of occlusion in the right middle cerebral artery and the bilateral common carotid arteries. HGF significantly reduced the infarct volume in a dose-dependent manner. In a separate series of experiments, we next histopathologically investigated both the anti-apoptotic effect on neurons and the angiogenetic effect of HGF. A large number of TUNEL positive neurons were observed in the inner boundary of the infarct area in both the control and the vehicle group whereas only a few TUNEL positive neurons were observed in the corresponding area in the HGF group. In the HGF group, Bcl-2 protein was obviously represented in surviving neurons subjected to ischemia. The number of the vascular lamina in HGF group were significantly higher than those in the vehicle group. These data suggest that HGF appears to have an ability to prevent apoptotic neuronal cell death while also possessing an angiogenetic effect in the central nervous system which was affected with transient focal cerebral ischemia.
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PMID:Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats. 1142 24

Hepatocyte growth factor (HGF) was originally discovered as a powerful mitogen for hepatocytes. HGF functions both as a neurotrophic factor as well as an angiogenetic factor. Furthermore, HGF has an anti-apoptotic effect on vascular endothelial cells. The present study examined the neuroprotective effect of HGF after transient focal cerebral ischemia in rats, in which an anti-apoptotic and an angiogenetic effect of HGF was assumed to contribute to the reduction of the infarct volume. The intraventricular administration of human recombinant HGF (90 micrograms) significantly reduced the infarct volume after 120 minutes occlusion of both the right middle cerebral artery (MCA) and the bilateral common carotid arteries (CCAs). In a separate series of experiments, we investigated both the anti-apoptotic effect on neurons and the angiogenetic effect of HGF histopathologically. The number of survival neurons and vascular lumina in the HGF group were significantly higher than those in the vehicle group. A large number of TUNEL positive neurons were observed in the inner boundary of the infarct area in the vehicle group, whereas only a few TUNEL positive neurons were observed in a corresponding area in the HGF group. In the HGF group, Bcl-2 protein was obviously represented in survival neurons as well as in vascular endothelial cells and in glial cells subjected to ischemia. These data suggest that HGF prevents apoptotic neuronal cell death by upregulating the production of Bcl-2 protein and by an angiogenetic effect in the central nervous system which affected transient focal cerebral ischemia.
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PMID:Hepatocyte growth factor reduces infarct volume after transient focal cerebral ischemia in rats. 1145 33

Alterations in factors involved in the regeneration of the neuronal network in the hippocampus of rats with microsphere embolism (ME) were examined. Nine hundred microspheres (48 microm in diameter) were injected into the right hemisphere, and immunochemical and immunohistochemical studies on the hippocampus were performed on the seventh day thereafter. Hematoxylin-eosin staining showed progressive and severe degeneration of the hippocampus after ME. The protein levels of brain-derived neurotrophic factor (BDNF), 43-kDa growth-associated protein (GAP-43), and adhesion protein L1 (L1) in the ipsilateral hippocampus of the ME animal, determined by Western blot analysis or enzyme immunoassay, were increased, unaltered, and decreased, respectively. In contrast, the immunohistochemical study showed increases in a marker of axonal sprouting GAP-43, and a neurotrophic factor BDNF, and a decrease in an adhesion molecule L1 in some areas of the hippocampal ischemic penumbra of such animals. These results suggest that some factors for regeneration of the neuronal network in the ischemic penumbra responded to sustained cerebral ischemia for a certain period, although functional network of the nerve cells in the microsphere-injected hemisphere would be unlikely established after ME.
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PMID:Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia. 1206 69

Hypoxic preconditioning provides protection against ischemic brain lesions in animal models of cerebral ischemia-hypoxia. To analyze the underlying molecular mechanisms, we developed an in vitro model of hypoxic neuroprotection in cerebellar granule neurons (CGN) by reducing the oxygen tension to 1-5% for 1-24 hr. Exposure to 5% O2 for 9 hr resulted in reduction of cell death after potassium deprivation, treatment with 100 microm glutamate, or 500 microm 3-nitroproprioninc acid (3-NP) by 46, 22, and 55%, respectively. Shorter (1 or 3 hr) or longer (>12 hr) intervals or pretreatment with lower oxygen tension failed to rescue CGN from death. In contrast, toxicity of four different chemotherapeutic drugs [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cisplatine, topotecane, and vincristine] was unaffected by hypoxic preconditioning. The induction of protective effects was dependent on new protein synthesis. Protein levels of B-cell lymphoma protein-2 (BCL-2), BCL-x(L/S), heat shock protein 70/90, and BCL-2-associated death protein remained unaltered. CGN incubated at 5% O2 for 9 hr showed increased levels of the vascular endothelial growth factor (VEGF), the VEGF receptor-2 (VEGFR-2), phosphorylated Akt/protein kinase B (PKB), and extracellular signal-regulated kinase 1 (ERK1). Incubation with a neutralizing anti-VEGF antibody, a monoclonal antibody to VEGFR-2, wortmannin, or antisense-Akt/PKB, but not treatment with U0126, an ERK-inhibitor, reverted the resistance acquired by hypoxic preconditioning. Inhibition of VEGFR-2 blocked the activation of Akt/PKB. Finally, pretreatment with recombinant VEGF resulted in a hypoxia-resistant phenotype in the absence of hypoxic preconditioning. Our data are indicating a sequential requirement for VEGF/VEGFR-2 activation and Akt/PKB phosphorylation for neuronal survival mediated by hypoxic preconditioning and propose VEGF as a hypoxia-induced neurotrophic factor.
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PMID:Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. 1215 19

Due to the development of molecular biology techniques, several types of neurotransmitter or neurotrophic factor secreting cell line can be established. These cell lines were grafted into the brain of animal models of Parkinson's disease and cerebral ischemia after encapsulating into the hollow fiber consisted of semipermeable membrane. Immunological reaction and tumor formation were prevented and functional effects were observed histologically, chemically and behaviorally. Current issues regarding encapsulated cell grafting are: delivery of neurotransmitter and neurotrophic factor simultaneously from one capsule, usage of human-derived cell lines and control of secretion from outside. There are two possible approaches regarding the usage of patient's own neural stem cells for regenerative therapy. Neural stem cells are collected from the subventricular zone of the lateral ventricle and these cells are differentiated into dopaminergic neurons using tyrosine hydroxylase induction cocktail (TH cocktail). Then, these neurons are grafted into the striatum of the patient. Another method is to inject TH cocktail into the patient's striatum in order to induce differentiation of dopaminergic neurons from the neural stem cells in vivo.
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PMID:[Intracerebral grafting of cell line or patient-derived neural stem cells for the treatment of neurological disorders]. 1278 89

Nutrient deprivation during ischemia leads to severe insult to neurons causing widespread excitotoxic damage in specific brain regions such as the hippocampus. One possible strategy for preventing neurodegeneration is to express therapeutic proteins in the brain to protect against excitotoxicity. We investigated the utility of equine infectious anemia virus (EIAV)-based vectors as genetic tools for delivery of therapeutic proteins in an in vivo excitotoxicity model. The efficacy of these vectors at preventing cellular loss in target brain areas following excitotoxic insult was also assessed. EIAV vectors generated to overexpress the human antiapoptotic Bcl-2 or growth factor glial-derived neurotrophic factor (GDNF) genes protected against glutamate-induced toxicity in cultured hippocampal neurons. In an in vivo excitotoxicity model, adult Wistar rats received a unilateral dose of the glutamate receptor agonist N-methyl-D-aspartate to the hippocampus that induced a large lesion in the CA1 region. Neuronal loss could not be protected by prior transduction of a control vector expressing beta-galactosidase. In contrast, EIAV-mediated expression of Bcl-2 and GDNF significantly reduced lesion size thus protecting the hippocampus from excitotoxic damage. These results demonstrate that EIAV vectors can be effectively used to deliver putative neuroprotective genes to target brain areas and prevent cellular loss in the event of a neurological insult. Therefore these lentiviral vectors provide potential therapeutic tools for use in cases of acute neurotrauma such as cerebral ischemia.
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PMID:Lentiviral-mediated delivery of Bcl-2 or GDNF protects against excitotoxicity in the rat hippocampus. 1558 9

Erythropoietin (EPO) is an acidic glycoprotein that was first detected as a hematopoietic factor and its synthesis is triggered in response to cellular hypoxia-sensing. EPO binds to type I cytokine receptors, which associate with the non-receptor tyrosine kinase Jak2, and thereby activate Stat 5a/5b, Ras/MAPK, and PI3-K/Akt signaling pathways. The recent discovery shows that there is a specific EPO/EPO-receptor system in the central nervous system (CNS), independently of the haematopoietic system. Hypoxia and anemia can up-regulate EPO/EPOR expressions in the CNS. Further studies demonstrate that EPO has substantial neuro-protective effects and acts as a neurotrophic factor on central cholinergic neurons, influencing their differentiation and regeneration. EPO also exerts neuro-protective activities in different models of brain damage in vivo and in vitro, such as hypoxia, cerebral ischaemia and sub-arachnoid haemorrhage. EPO may also be involved in synaptic plasticity via the inhibition or stimulation of various neurotransmitters. Therefore, human recombinant EPO that activate its receptors in the central nervous system might be utilized in the future clinical practice involving neuroprotection and brain repair.
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PMID:[Hematopoietic growth factor EPO has neuro-protective and neuro-trophic effects--review]. 1585 5

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

Organotypic hippocampal slice cultures represent a feasible model for studies of cerebral ischemia and the role of ionotropic glutamate receptors in oxygen-glucose deprivation-induced neurodegeneration. New results and a review of existing data are presented in the first part of this paper. The role of glutamate transporters, with special reference to recent results on inhibition of glutamate transporters under normal and energy-failure (ischemia-like) conditions is reviewed in the last part of the paper. The experimental work is based on hippocampal slice cultures derived from 7 day old rats and grown for about 3 weeks. In such cultures we investigated the subfield neuronal susceptibility to oxygen-glucose deprivation, the type of induced cell death and the involvement of ionotropic glutamate receptors. Hippocampal slice cultures were also used in our studies on glutamate transporters reviewed in the last part of this paper. Neurodegeneration was monitored and/or shown by cellular uptake of propidium iodide, loss of immunocytochemical staining for microtubule-associated protein 2 and staining with Fluoro-Jade B. To distinguish between necrotic vs. apoptotic neuronal cell death we used immunocytochemical staining for active caspase-3 (apoptosis indicator) and Hoechst 33342 staining of nuclear chromatin. Our experimental studies on oxygen-glucose deprivation confirmed that CA1 pyramidal cells were the most susceptible to this ischemia-like condition. Judged by propidium iodide uptake, a selective CA1 lesion, with only minor affection on CA3, occurred in cultures exposed to oxygen-glucose deprivation for 30 min. Nuclear chromatin staining by Hoechst 33342 and staining for active caspase-3 showed that oxygen-glucose deprivation induced necrotic cell death only. Addition of 10 microM of the N-methyl-D-aspartate glutamate receptor antagonist MK-801, and 20 microM of the non-N-methyl-D-aspartate glutamate receptor antagonist 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline to the culture medium confirmed that both N-methyl-D-aspartate and non-N-methyl-D-aspartate ionotropic glutamate receptors were involved in the oxygen-glucose deprivation-induced cell death. Glutamate is normally quickly removed, from the extracellular space by sodium-dependent glutamate transporters. Effects of blocking the transporters by addition of the DL-threo-beta-benzyloxyaspartate are reviewed in the last part of the paper. Under normal conditions addition of DL-threo-beta-benzyloxyaspartate in concentrations of 25 microM or more to otherwise untreated hippocampal slice cultures induced neuronal cell death, which was prevented by addition of 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801. In energy failure situations, like cerebral ischemia and oxygen-glucose deprivation, the transporters are believed to reverse and release glutamate to the extracellular space. Blockade of the transporters by a subtoxic (10 microM) dose of DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation (but not during the next 48 h after oxygen-glucose deprivation) significantly reduced the oxygen-glucose deprivation-induced propidium iodide uptake, suggesting a neuroprotective inhibition of reverse transporter activity by DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation under these conditions. Adding to this, other results from our laboratory have demonstrated that pre-treatment of the slice cultures with glial cell-line derived neurotrophic factor upregulates glutamate transporters. As a logical, but in some glial cell-line derived neurotrophic factor therapy-related conditions clearly unwanted consequence the susceptibility for oxygen-glucose deprivation-induced glutamate receptor-mediated cell death is increased after glial cell-line derived neurotrophic factor treatment. In summary, we conclude that both ionotropic glutamate receptors and glutamate transporters are involved in oxygen-glucose deprivation-induced necrotic cell death in hippocampal slice cultures, which have proven to be a feasible tool in experimental studies on this topic.
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PMID:Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen-glucose deprivation of hippocampal slice cultures. 1634 51


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