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

Erythropoietin (Epo) plays a central role in erythropoiesis but also has neuroprotective properties. Recently, Epo-related neuroprotective studies used a hypoxic-ischemic neonatal model, which is different from focal stroke, a frequent cause of neonatal brain injury. We report on the effects of Epo treatment given after focal stroke and its potential neuroprotective mechanisms in postnatal day 7 rats with focal cerebral ischemia (FCI) achieved by occlusion of the middle cerebral artery. The experimental groups included sham operation, FCI plus vehicle, and FCI plus Epo. In the Epo-treated group, pups received a single intraperitoneal injection of 1000 U/kg 15 min after FCI or three injections of 100, 1000, or 5000 U/kg, starting at 15 min and repeated at 1 and 2 d after FCI. Epo treatment produced significant reductions in the mean infarct area and volume at 1 and 3 d after FCI, demonstrated by 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining showed a markedly reduced number of TUNEL-positive cells in the Epo-treated group when compared with the vehicle control 3 d after FCI (p<0.01). The most effective dose after FCI was 1000 U/kg for 3 d. Immunoanalyses showed that Epo induced a significant increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription-5 expressions at 1 and 3 d and up-regulated Bcl-xL expression by 24 h after FCI but did not affect Epo receptor or NF-kappaB expression. In conclusion, Epo given after FCI in neonatal rats provides significant neuroprotection, mediated possibly by activation of the Janus kinase-signal transducer and activator of transcription-Bcl-xL signaling pathways.
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PMID:Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. 1571 73

Understanding the tissue distribution of erythropoietin receptors and cellular actions of erythropoietic agents may facilitate the development of wider applications for these compounds. Erythropoietin receptors have been identified in the central nervous system (CNS), retina, heart, vascular endothelium, kidney, lung, liver, gastrointestinal and reproductive tracts, and erythroid bone marrow precursors. Potential benefits of erythropoietic agents in several therapeutic areas may result from actions other than hematopoiesis stimulation. Their hematopoietic effects may also have broader applications in treating anemia of the elderly and non-chemotherapy (CT)-related anemia in patients with cancer. Furthermore, because hypoxic tumor cells tend to be more resistant to radiation therapy (RT) and some forms of CT, and more aggressive than normoxic cells, increased oxygenation resulting from anemia correction may increase RT and CT sensitivity, possibly impacting treatment outcomes. However, clinical studies addressing this hypothesis have conflicting results. Preliminary evidence suggests erythropoietin has CNS neuroprotective effects, including potential clinical benefits in ischemic stroke. In addition, data suggest that erythropoietin (epoetin alfa) may attenuate declines in cognitive function during CT for early-stage breast cancer. Erythropoietin may have benefits in retinal disease, peripheral neuropathy, and myocardial ischemia. Thus, accumulating evidence suggests that erythropoietic agents may have clinical utility outside CT-related anemia.
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PMID:Preclinical and clinical studies: a preview of potential future applications of erythropoietic agents. 1576 75

Erythropoietin mediates an evolutionarily conserved, ancient immune response that limits damage to the heart, the nervous system and other tissues following injury. New evidence indicates that erythropoietin specifically prevents the destruction of viable tissue surrounding the site of an injury by signalling through a non-haematopoietic receptor. Engineered derivatives of erythropoietin that have a high affinity for this receptor have been developed, and these show robust tissue-protective effects in diverse preclinical models without stimulating erythropoiesis. A recent successful proof-of-concept clinical trial that used erythropoietin to treat human patients who had suffered a stroke encourages the evaluation of both this cytokine and non-erythropoietic derivatives as therapeutic agents to limit tissue injury.
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PMID:Emerging biological roles for erythropoietin in the nervous system. 1592 18

Erythropoietin (EPO) is neuroprotective in models of stroke and traumatic brain injury (TBI) when administered prior to or within the first few hours after injury. We seek to demonstrate that EPO also has neurorestorative effects when administered late (i.e., 1 day) after TBI in the rat. Twelve rats were subjected to TBI. Six rats were treated with EPO daily for 14 days starting 1 day after injury, and an additional six rats were treated with saline. Bromodeoxyuridine (BrdU) was administered daily for 14 days. Memory tests using a Morris Water Maze were performed prior to and after injury and treatment. Animals were sacrificed at 15 days after TBI, and their brains were prepared for histological analysis of damage to the dentate gyrus (DG) and for evaluation of newly formed neurons using double labeling of BrdU and MAP-2. The data revealed a significant improvement in spatial memory and significant increase in the number of newly formed neurons with EPO treatment compared with control animals. These data suggest that EPO treatment initiated 1 day after TBI is neurorestorative by enhancing neurogenesis, as well as neuroprotective.
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PMID:Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. 1615 16

Erythropoietin is a hypoxia-induced hormone that is a major regulator of normal erythropoiesis. Over the last decade, the production of recombinant human erythropoietin has revolutionized the treatment of anemia associated with chronic renal failure, and has led to a greater understanding of anemia pathophysiology and to the elucidation of the interactions of erythropoietin, iron, and erythropoiesis. Anemia has been shown to be independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia have expanded considerably the indications of erythropoietin use in various patient populations and are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia. The results of such treatment are promising in a variety of new clinical settings, including anemia associated with congestive heart failure. Furthermore, the erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes and preclinical studies have established erythropoietin to be a pleiotropic cytokine with anti-apoptotic activity and tissue-protective actions in the cardiovascular system, beyond correction of hemoglobin levels. Despite some potential adverse effects, such as hypertension, and the occurrence of erythropoietin resistance, early studies in heart failure patients with anemia suggest that erythropoietin therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Anemia is found in about one-third of all cases of congestive heart failure (CHF). The most likely common cause is chronic renal insufficiency, which is present in about half of all CHF cases. However, anemia can occur in CHF without renal insufficiency and is likely to be due to excessive cytokine production. The anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Long-standing anemia of any cause can cause left ventricular hypertrophy, which can lead to cardiac cell death through apoptosis and worsen CHF. Therefore, a vicious circle, cardio-renal anemia syndrome, is set up wherein CHF causes anemia, and the anemia causes more CHF and both damage the kidneys worsening the anemia and the CHF further and increasing mortality. There is now evidence that early correction of the CHF anemia with subcutaneous erythropoietin and intravenous iron improves shortness of breath and fatigue, cardiac function, renal function and exercise capacity, reducing the need for hospitalization and improving quality of life. In the present review we discuss the data on current clinical use of erythropoietin in cardiovascular disease, with the main focus on the treatment of congestive heart failure, and summarize the advances and progress made in the understanding of the hematopoietic and pleiotropic effects of erythropoietin in the cardiovascular system.
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PMID:Erythropoietin in heart failure and other cardiovascular diseases: hematopoietic and pleiotropic effects. 1624 29

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

The incidence of both congestive heart failure (CHF) and end-stage renal disease both are increasing. Anemia is common in both conditions and is associated with a marked increase in mortality and morbidity in both CHF and chronic kidney insufficiency (CKI). Each of these 3 conditions can cause or worsen the other 2. In other words, a vicious circle frequently is present in which CHF can cause or worsen both anemia and CKI, in which CKI can cause or worsen both anemia and CHF, and in which anemia can cause or worsen both CHF and CKI. We have called this vicious circle the cardio renal anemia syndrome. Optimal treatment of CHF with all the recommended CHF medications at their recommended doses will, in our experience, frequently fail to improve the CHF and CKI if anemia is present and is not corrected. On the other hand, correction of the anemia with subcutaneous erythropoietin and intravenous iron has caused a great improvement in the CHF including a marked improvement in patient and cardiac function and a marked reduction in the need for hospitalization and for high-dose diuretics. It also frequently has caused renal function to improve or at least stabilize. In addition, patients' quality of life and exercise capacity also have improved with the correction of the anemia. In CKI patients, anemia also may play an important role in increasing the risk for death, coronary heart disease, stroke, and progression to end-stage renal disease. Erythropoietin may have a direct positive effect on the heart and brain unrelated to correction of the anemia by reducing cell apoptosis and by increasing neovascularization, both of which could prevent tissue damage. This could have profound therapeutic implications not only in CHF but in the future treatment of myocardial infarction, coronary heart disease, strokes, and renal failure.
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PMID:Erythropoietin in heart failure. 1629 62

Ischemic preconditioning (IP) protects the brain from subsequent, prolonged, and lethal ischemia in experimental studies. Erythropoietin (EPO) participates in the brain's intrinsic response to injury and may play a role in preconditioning. By using a middle cerebral artery occlusion (MCAo) model of transient ischemic attack (TIA), we sought to determine whether EPO is required for IP in the protective response against focal ischemic stroke. Rats underwent three 10-min MCA occlusions or sham surgery. Three days later, animals underwent 2 hr of MCAo and 22 hr of reperfusion. Experimental TIAs reduced infarct volumes by 55% (P < 0.05), inhibited DNA fragmentation, and improved neurological outcome by 50% (P < 0.05) after ischemic stroke. EPO and its receptor were up-regulated by IP in the ipsilateral hemisphere by 24 hr after IP, before ischemic stroke and soluble EPO receptor attenuated neuroprotection by IP (88% reduction, P < 0.05). Pretreatment with the PI-3 kinase inhibitor wortmannin abolished the protective effect of IP against ischemic injury (P < 0.05). IP may be mediated in part by EPO through a PI-3 kinase pathway.
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PMID:Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack. 1630 46

Cell death induced by the combined insult of hypoxia-ischemia in neonatal rodents has been extensively investigated. Ischemia-only-induced cell death, however, has been much less characterized. Based on the notion that 1) ischemic stroke is a relatively common disorder in human neonates, and 2) developing cells are more susceptible to apoptosis, the present study examined whether typical apoptosis was induced by cerebral ischemia in a new neonatal rat model. Erythropoietin (EPO; Epoetin) was tested for its protective effect against ischemia-induced cell death. Postnatal day 7 rats were subjected to permanent occlusion of the middle cerebral artery branch supplying the right whisker-barrel cortex. Terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeled-positive cells in the ischemic region were detectable 4 h after ischemia and reached a peak level 16 h later. The cell death was preceded by caspase activation and cytochrome c release. Cell body shrinkage was evident among damaged cells. Agarose gel electrophoresis showed DNA damage with a smear pattern as well as DNA laddering. Electron microscopy demonstrated apoptotic features such as cell shrinkage, chromatin condensation, and fragmentation; meanwhile, necrotic alterations coexisted in the cytoplasm. EPO treatment increased signal transducers and activators of transcription-5 and Bcl-2 levels, markedly attenuated apoptotic cell death, and reduced ischemic infarct in the cortex. It is suggested that focal ischemia in the developing brain causes cell death with prominent apoptotic features coexisting with some characteristics of necrosis. This is consistent with the concept of hybrid death described previously in cultures and adult or developing brain. EPO may be explored as a potential therapy for neonatal ischemic stroke.
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PMID:Cell death mechanism and protective effect of erythropoietin after focal ischemia in the whisker-barrel cortex of neonatal rats. 1635 10

Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis. Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult neurogenesis and for migration of regenerating neurons during post-injury recovery.
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PMID:A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. 1643 14


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