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

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major clinical problem causing cerebral ischemia and infarction. The pathogenesis of vasospasm is related to a number of pathological processes including endothelial damage and alterations in vasomotor function leading to narrowing of arterial diameter and a subsequent decrease in cerebral blood flow. Discovery of the tissue protective effects of erythropoietin (EPO) stimulated the search for therapeutic application of EPO for the prevention and treatment of cerebrovascular disease. Recent studies have identified the role of EPO in vascular protection mediated by the preservation of endothelial cell integrity and stimulation of angiogenesis. In this review, we discuss the EPO-induced activation of endothelial nitric oxide (NO) synthase and its contribution to the prevention of cerebral vasospasm.
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PMID:Erythropoietin and cerebral vascular protection: role of nitric oxide. 1704 12

Restoration of local blood supply in the post-ischemic brain plays a critical role in tissue repair and functional recovery. The present investigation explored beneficial effects of recombinant human erythropoietin (rhEPO) on vascular endothelial cell survival, angiogenesis, and restoration of local cerebral blood flow (LCBF) after permanent focal cerebral ischemia in adult mice. Saline or rhEPO (5,000 U/kg, intraperitoneal) was administered 30 mins before ischemia and once daily after ischemic stroke. Immunohistochemistry showed an enhancing effect of rhEPO on expression of EPO receptor (EPOR) of endothelial cells in the penumbra region 3 to 21 days after the ischemic insult. The treatment with rhEPO decreased ischemia-induced cell death and infarct volume 3 days after stroke. Specifically, rhEPO reduced the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling- and caspase-3-positive endothelial cells in the penumbra region. Colocalization of the vessel marker glucose transporter-1 (Glut-1) and cell proliferation marker 5-bromo-2'-deoxyuridine indicated enhanced angiogenic activity in rhEPO-treated mice 7 to 21 days after stroke. Western blot showed upregulation of the expression of angiogenic factors Tie-2, Angiopoietin-2, and vascular endothelial growth factor in rhEPO-treated animals. Local cerebral blood flow was measured by laser scanning imaging 3 to 21 days after stroke. At 14 days, LCBF in the penumbra was recovered to preischemia levels in rhEPO-treated mice but not in control mice. Our data suggest that rhEPO treatment upregulates the EPOR level in vascular endothelial cells, confers neurovascular protection, and enhances angiogenesis. We further show a promoting effect of rhEPO on LCBF recovery in the ischemic brain. These rhEPO-induced effects may contribute to therapeutic benefits in the treatment of ischemic stroke.
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PMID:Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice. 1707 15

One approach for developing targeted stroke therapies is to identify the neuronal protective and destructive signaling pathways and gene expression that follow ischemic insult. In some neural injury models, the transforming growth factor-beta family member activin can provide neuroprotective effects in vivo and promote neuronal survival. This study tests if activin supports cortical neurons after ischemic challenge in vitro and if signals after cerebral ischemia involve activin in vivo. In a defined cell culture model that uses hydrogen peroxide (H(2)O(2))-free radical stress, activin addition maintained neuronal survival. H(2)O(2) treatment increased activin mRNA twofold in surviving cortical neurons, and inhibition of activin with neutralizing antibodies caused neuronal death. These data identify activin gene changes as a rapid response to oxidative stress, and indicate that endogenous activin acts as a protective factor for cortical neurons in vitro. Similarly, after transient focal cerebral ischemia in adult mice, activin mRNA increased at 1 and 4 h ipsilateral to the infarct but returned to control values at 24 h after reperfusion. Intracellular activated smad signals were detected in neurons adjacent to the infarct. Activin was also increased after 2 h of 11% hypoxia. Activin mRNA increased at 1 h but not 4 or 24 h after hypoxia, similar to the time course of erythropoietin and vascular endothelial growth factor induction. These findings identify activin as an early-regulated gene response to transient ischemia and hypoxia, and its function in cortical neuron survival during oxidative challenge provides a basis to test activin as a potential therapeutic in stroke injury.
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PMID:Activin is a neuronal survival factor that is rapidly increased after transient cerebral ischemia and hypoxia in mice. 1713 27

Cerebral ischemia disrupts the neurovascular unit, involving death of neuronal, glial, and endothelial cells (ECs) in the core and penumbra regions. Whereas the neuroprotective effect of recombinant human erythropoietin (rhEPO) has been widely investigated, its effects on ECs remain elusive. We now report the effects of rhEPO treatment on EC death and neurovasculature repair following a focal ischemic stroke in postnatal day 7 neonatal rats. rhEPO (5000 U/kg i.p.) was administered 60 min after ischemia and for the next 3 days. Western blot analysis revealed increased expression of neurovascular remodeling proteins, including Tie-1, angiopoietin-2, and basic fibroblast growth factor in rhEPO-treated pups. rhEPO treatment significantly reduced EC death in the ischemic penumbra region 12 to 72 h after ischemia examined by immunostaining of terminal deoxynucleotidyl transferase dUTP nick-end labeling and EC marker glucose transporter-1 (GLUT-1). Treatment with rhEPO increased proliferation of ECs and neuronal cells, revealed by costaining of 5-bromo-2'-deoxyuridine with GLUT-1 or with the neuronal marker protein (NeuN) 7 to 21 days after stroke. Specifically, rhEPO increased number of NeuN-positive cells in close proximity to proliferating microvessels. These results suggest for the first time that, in addition to its protection on neural cells, EPO protects ECs and promotes the neurovascular unit repair, which may contribute to its therapeutic benefits after neonatal ischemic stroke.
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PMID:The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats. 1749 64

We previously reported that peroxiredoxin 2 (PRDX2) and Cu/Zn superoxide dismutase 1 (SOD1) proteins are up-regulated in rat primary neuronal cultures following erythropoietin (EPO) preconditioning. In the present study, we have demonstrated that adenovirally mediated overexpression of PRDX2 in cortical neuronal cultures can protect neurons from in vitro ischemia (oxygen-glucose deprivation) and an oxidative insult (cumene hydroperoxide) but not glutamate excitotoxicity. We have also demonstrated that adenovirally mediated overexpression of SOD1 in cortical neuronal cultures protected neurons only against the oxidative insult. Interestingly, we did not detect up-regulation of PRDX2 or SOD1 protein in the rat hippocampus following exposure to either 3 min or 8 min of global cerebral ischemia. Further characterization of PRDX2's neuroprotective mechanisms may aid in the development of a neuroprotective therapy.
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PMID:Peroxiredoxin 2 overexpression protects cortical neuronal cultures from ischemic and oxidative injury but not glutamate excitotoxicity, whereas Cu/Zn superoxide dismutase 1 overexpression protects only against oxidative injury. 1766 78

Uncontrolled expression of vascular endothelial growth factor (VEGF) in vivo may cause unexpected side effects, such as brain hemangioma or tumor growth. Because hypoxia-inducible factor-1 (HIF-1) is upregulated during cerebral ischemia and regulates gene expression by binding to a cis-acting hypoxia-responsive element (HRE), we therefore used a novel HRE, originating in the 3'-end of the erythropoietin (Epo) gene, to control gene expression in the ischemic brain. A concatemer of nine copies (H9) of the consensus sequence of HRE was used to mediate hypoxia induction. Three groups of adult CD-1 mice received AAVH9-VEGF, AAVH9-lacZ or saline injection, and then underwent 45 min of transient middle cerebral artery occlusion (tMCAO). Results show that HIF-1 was persistently expressed in the ischemic brain. VEGF was overexpressed in the ischemic perifocal region in AAVH9-VEGF-transduced mice. Double-labeled immunostaining showed that VEGF expressed in neurons and astrocytes but not endothelial cells, suggesting that adeno-associated virus (AAV) vectors transduced neurons and astrocytes predominantly. The total number of microvessels/enlarged microvessels was greatly increased in the AAVH9-VEGF-transduced mice (180+/-29/27+/-4) compared to the AAVH9-lacZ (118+/-19/14+/-3) or saline-treated (119+/-20/14+/-2) mice after tMCAO (P<0.05). Cell proliferation examination demonstrated that these microvessels were newly formed. Regional cerebral blood flow recovery in the AAVH9-VEGF-transduced mice was also better than in AAVH9-lacZ or saline-treated mice (P<0.05). Our data indicated that HRE is a novel trigger for the control of VEGF expression in the ischemic brain. VEGF overexpression through AAVH9-VEGF gene transfer showed stable focal angiogenic effects in post-ischemic repair process, providing an opportunity to rebuild injured brain tissue.
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PMID:Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer promotes angiogenesis following focal cerebral ischemia in mice. 1796 Jan 59

We studied the effect of hyperbaric oxygen (HBO) preconditioning on the molecular mechanisms of neuroprotection in a rat focal cerebral ischemic model. Seventy-two male Sprague-Dawley rats were pretreated with HBO (100% O(2), 2 atmospheres absolute, 1 h once every other day for 5 sessions) or with room air. In experiment 1, HBO-preconditioned rats and matched room air controls were subjected to focal cerebral ischemia or sham surgery. Postinjury motor parameters and infarction volumes of HBO-preconditioned rats were compared with those of controls. In experiment 2, HBO-preconditioned rats and matched room air controls were killed at different time points. Brain levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream target gene erythropoietin (EPO) analyzed by Western blotting and RT-PCR as well as HIF-1alpha DNA-binding and transcriptional activities were determined in the ipsilateral hemisphere. HBO induced a marked increase in the protein expressions of HIF-1alpha and EPO and the activity of HIF-1alpha, as well as the expression of EPO mRNA. HBO preconditioning dramatically improved the neurobehavioral outcome at all time points (3.0 +/- 2.1 vs. 5.6 +/- 1.5 at 4 h, 5.0 +/- 1.8 vs. 8.8 +/- 1.4 at 8 h, 6.4 +/- 1.8 vs. 9.7 +/- 1.3 at 24 h; P < 0.01, respectively) and reduced infarction volumes (20.7 +/- 4.5 vs. 12.5 +/- 3.6%, 2,3,5-Triphenyltetrazolium chloride staining) after cerebral ischemia. This observation indicates that the neuroprotection induced by HBO preconditioning may be mediated by an upregulation of HIF-1alpha and its target gene EPO.
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PMID:Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1alpha and erythropoietin in rats. 1817 94

Many studies showed beneficial effects of either erythropoietin (EPO) or mesenchymal stem cells (MSCs) treatment in cerebral ischemia. In addition to a neuroprotective role, not only EPO but also MSC favors neurogenesis and functional recovery. In an attempt to further improve postischemic tissue repair, we investigated the effect of a systemic administration of MSC, in the presence or not of EPO, on neurogenesis and functional recovery in a transient focal cerebral ischemia model in the adult rat. Twenty-four hours after ischemia, the rats were divided into four groups, namely vehicle, MSC, EPO, and MSC+EPO, and received a single intravenous injection of MSC (2 x 10(6) cells) and/or a repeated intraperitoneal administration of EPO (1,000 UI/kg) for 3 days. The lesion volume, the MSC outcome, neurogenesis, and functional recovery were assessed 51 days after ischemia. The results showed that cellular proliferation and neurogenesis were increased along the lateral ventricle wall in the MSC+EPO group, whereas no significant effect was observed in groups receiving MSC or EPO alone. This effect was accompanied by an improvement of mnesic performances. Mesenchymal stem cells expressing neuronal or glial markers were detected in the ischemic hemisphere. These results suggest that EPO could act in a synergistic way with MSC to potentiate the postischemic neurogenesis.
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PMID:Combined therapeutic strategy using erythropoietin and mesenchymal stem cells potentiates neurogenesis after transient focal cerebral ischemia in rats. 1847 23

1. Asialoerythropoietin (aEPO), a derivative of cytokine erythropoietin, has been shown to have neuroprotective effects without haematological complications when administered in single or repeated doses. The present study examines our hypothesis that aEPO may provide neuroprotection against programmed apoptotic cell death when administered in a continuous low dose. 2. Focal cerebral ischaemia was introduced by occlusion of the middle cerebral artery using a surgically placed intraluminal filament in young male Sprague Dawley rats (9 weeks old). After 90 min ischaemia, reperfusion was established by filament removal. Both study and control groups had implanted osmotic minipumps through which they received either aEPO (1 microL/h; 20 microg/kg per 24 h) or normal saline (1 microL/h) for 4 days. On Day 4, infarct volume, the number of apoptotic cells and concentrations of activated caspase 3 and 9 were evaluated in the penumbra region. 3. Asialoerythropoietin was detected in the cerebrospinal fluid of the study group, whereas none was detected in the control group. Although there were no significant changes in haematocrit levels or behaviour scores (on Days 1 and 4) between the study and control groups, aEPO administration significantly reduced infarct volume in the study group compared with the control group (168 +/- 19 vs 249 +/- 28 mm(3), respectively; P < 0.05). 4. The number of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL)-positive cells and the concentration of activated caspase 3 and 9 in the penumbra region were significantly lower in the study group compared with the control group. 5. In conclusion, our data suggest that aEPO provides a short-term, possibly histological, protection in young adult male rats when administered immediately after reperfusion.
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PMID:Effect of continuous infusion of asialoerythropoietin on short-term changes in infarct volume, penumbra apoptosis and behaviour following middle cerebral artery occlusion in rats. 1965 Jul 97

Improving the ability of the kidney to tolerate injury through preconditioning is likely to have important clinical implications. Although a number of preconditioning strategies have been studied, ischemic preconditioning (IP) has been studied the most experimentally. The information gathered has helped us shed more light into the mechanisms responsible for this tissue adaptation that confers to tissues a more resistant status. IP is effective within minutes, suggesting that preformed mediators are involved. This is followed by delayed preconditioning, a phenomenon that is less potent but longer acting. Remote preconditioning occurs also in non-affected tissues and can be transferable. A number of mediators and transcription factors have been implicated including kinases, heat shock proteins, nitric oxide and neurogenic pathways, all of which help change the cell into a more resistant phenotype. There is evidence that IP also occurs in the human environment with lessons learned from myocardial ischemia, hepatic resection and cerebral ischemia. Because of the ethical impediment with intentionally applying organ ischemia, there has been an interest in pharmacological preconditioning lately. Exogenously administered erythropoietin was shown to benefit kidneys subjected to different insults. In addition, mesenchymal stem cells-based approaches for the prevention and treatment of acute kidney injury (AKI) are being studied. Calcineurin inhibitors may represent a viable way to reduce ischemia reperfusion injury in transplantation. Translating the experimental findings to the clinical arena remains a challenge. The discovery of new biomarkers for AKI should help initiate therapy early, when therapy could make a difference.
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PMID:Preconditioning: from experimental findings to novel therapies in acute kidney injury. 1977 19


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