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

The primary function of the glycoprotein hormone erythropoietin (Epo) is to promote red cell production by inhibiting apoptosis of erythrocytic progenitors in hemopoietic tissues. However, functional Epo receptors (Epo-R) have recently been demonstrated in various nonhemopoietic tissues indicating that Epo is a more pleiotropic viability and growth factor. Herein, in vitro and in vivo effects of Epo in the brain and the cardiovascular system are reviewed. In addition, the therapeutic impact of Epo in oncology is considered, including the question of whether Epo might promote tumor growth. Convincing evidence is available that Epo acts as a neurotrophic and neuroprotective factor in the brain. Epo prevents neuronal cells from hypoxia-induced and glutamate-induced cell death. Epo-R is expressed by neurons and glia cells in specific regions of the brain. Epo supports the survival of neurons in the ischemic brain. The neuroprotective potential of Epo has already been confirmed in a clinical trial on patients with acute stroke. With respect to the vasculature, Epo acts on both endothelial and smooth muscle cells. Epo promotes angiogenesis and stimulates the production of endothelin and other vasoactive mediators. In addition, Epo-R is expressed by cardiomyocytes. The role of Epo as a myocardial protectant is at the focus of present research. Epo therapy in tumor patients is practiced primarily to maintain the hemoglobin concentration above the transfusion trigger and to reduce fatigue. In addition, increased tumor oxygenation may improve the efficacy of chemotherapy and radiotherapy. However, tumor cells often express Epo-R. Therefore, careful studies are required to fully exclude that recombinant human Epo (rHuEpo) promotes tumor growth.
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PMID:Beneficial and ominous aspects of the pleiotropic action of erythropoietin. 1532 61

Erythropoiesis usually fails during severe illness because of a blunting of the kidney-erythropoietin (EPO)-bone marrow axis. In this setting, clinical studies have shown that recombinant human erythropoietin (rhEPO), administered in pharmacological amounts, significantly reduces the need for blood transfusions. In addition to the kidney, however, EPO is also produced locally by other tissues in a paracrine-autocrine manner. Here, similar to its role in the bone marrow, EPO rescues cells from apoptosis. Additionally, EPO reduces inflammatory responses, restores vascular autoregulation, and promotes healing. The results of many studies (including a phase II clinical trial in ischemic stroke) demonstrate that rhEPO protects the brain, spinal cord, retina, heart, and kidney from ischemic and other types of injury. Although rhEPO is efficacious in the treatment of EPO-deficient anemia during illness, inadequate effort has been devoted to determining whether direct tissue protection might also result from its administration. Here, we speculate on the potential utility of EPO as a protective cytokine in the context of acute critical illness and suggest key parameters required for a proof-of-concept clinical study.
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PMID:Science review: recombinant human erythropoietin in critical illness: a role beyond anemia? 1546 92

In addition to its well-known erythropoetic effect, erythropoietin (EPO) has also been shown to be neuroprotective in various animal models. In contrast to EPO, carbamylated EPO (CEPO) does not bind to the EPO receptor on UT7 cells or have any haematopoietic/proliferative activity on these cells. In vivo studies in mice and rats showed that even high doses of CEPO for long periods are not erythropoietic. However, in common with EPO, CEPO does inhibit the apoptosis associated with glutamate toxicity in hippocampal cells. Like EPO, CEPO is neuroprotective in a wide range of animal models of neurotoxicity: middle cerebral artery occlusion model of ischaemic stroke, sciatic nerve compression, spinal cord depression, experimental autoimmune encephalomyelitis and peripheral diabetic neuropathy. To date, EPO and CEPO have been exciting developments in the quest for the treatment of various types of neurotoxicity. The development of CEPO should continue.
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PMID:A neuroprotective derivative of erythropoietin that is not erythropoietic. 1550 Mar 99

Studies have suggested that erythropoietin (EPO) may be used to treat stroke in both animals and humans. It is thought to exert its effects directly on the brain and studies with therapeutic doses have shown that it can cross the blood-brain barrier. Here, we compared in a blinded fashion the ability of three erythropoietic agents (murine erythropoietin, human erythropoietin, and darbepoetin alfa, an analog of human erythropoietin in clinical use) to cross the blood-brain barrier of the mouse. High-performance liquid chromatography (HPLC) results showed that all three erythropoietic agents were enzymatically resistant in brain and blood. The unidirectional blood-to-brain influx rates (Ki) as measured by multiple-time regression analysis showed that all the erythropoietic agents crossed the blood-brain barrier at about the same rate as albumin, suggesting that they cross the blood-brain barrier by way of the extracellular pathways. No saturable component to influx was found, but indirect evidence suggested a brain-to-blood efflux system. The percent of the intravenously injected dose taken up per gram of brain (%Inj/g) ranged from 0.05 to 0.1 %Inj/g among the three erythropoietic agents and peaked about 3 h after IV injection. For other substances, this range of %Inj/g is known to produce direct effects on brain function. We conclude that erythropoietic agents cross the blood-brain barrier by way of the extracellular pathways in amounts that are likely sufficient to explain their neuroprotective effects.
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PMID:Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. 1555 41

Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective activity upon reduced oxygenation or ischemia of brain, retina, and spinal cord. To examine whether Epo has an impact on the retrograde degeneration of retinal ganglion cells (RGCs) following optic nerve transection in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo preferentially in neuronal cells without inducing polycythemia. We show that the tg21 retina expresses human Epo and that RGCs in this mouse line carry the Epo receptor. Upon axotomy, the RGCs of Epo transgenic tg21 mice were protected against degeneration, as compared with wild-type control animals. Western blot analysis revealed decreased phosphorylation levels of STAT-5 and reduced expression of Bcl-XL in RGCs of axotomized tg21 animals, suggesting that the corresponding pathways are not crucial for Epo's neuroprotective activity. Increased phosphorylation levels of ERK-1/-2 and Akt, as well as decreased caspase-3 activity, however, were observed in injured tg21 retinae. Injection of selective inhibitors of ERK-1/-2 (PD98059) or Akt (Wortmannin) pathways into the vitreous space revealed that transgenic Epo protected the RGCs by a pathway involving ERK-1/-2 but not Akt. In view that axotomy-induced degeneration of RGC occurs slowly, and considering the earlier data on the safety and efficacy of Epo in human stroke patients, we predict the clinical implementation of recombinant human Epo not only in patients with acute ischemic stroke, but also with more delayed degenerative neurological diseases.
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PMID:Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. 1555 72

Erythropoietin (EPO) is the primary regulator of erythropoiesis, stimulating growth, preventing apoptosis, and promoting differentiation of red blood cell progenitors. The EPO receptor belongs to the cytokine receptor superfamily. Although the primary role of EPO is the regulation of red blood cell production, EPO and its receptor have been localized to several nonhematopoietic tissues and cells, including the central nervous system (CNS), endothelial cells, solid tumors, the liver, and the uterus. The presence of EPO receptors and the possibility of EPO signaling in these tissues and cells have led to numerous studies of the effects of EPO at these sites. In particular, expression of EPO and the EPO receptor in cancer cells has generated much interest because of concern that administration of recombinant human erythropoietin (rHuEPO) to patients with breast and other cancer cells expressing the EPO receptor may promote tumor growth via the induction of cell proliferation or angiogenesis. However, evidence supporting a growth-promoting effect has been inconclusive. Moreover, several preclinical studies have shown a beneficial effect of EPO on delaying tumor growth. Further, it is conceivable that increased expression of EPO could reduce tumor hypoxia and ameliorate the deleterious effects of hypoxia on tumor growth, metastasis, and treatment resistance. On the other hand, EPO has also been shown to produce an angiogenic effect in vascular endothelial cells in vitro. However, there is no evidence that these effects occur in vivo to promote tumor growth. EPO and EPO receptors are expressed in neural tissue, and they are upregulated there by hypoxia. Animal studies have shown that administration of epoetin alfa (an rHuEPO) reduces tissue injury due to ischemic stroke, blunt trauma, and experimental autoimmune encephalomyelitis. These findings suggest that epoetin alfa may provide a therapeutic benefit in patients with stroke, trauma, epilepsy, and other CNS-related disorders. Clearly, further study of EPO and the EPO receptor in nonhematopoietic tissue is warranted to determine the potential therapeutic usefulness of rHuEPO as well as to determine the signaling pathway responsible for its effect in vivo.
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PMID:The erythropoietin receptor and its expression in tumor cells and other tissues. 1559 19

Anemia is found in about one-third of all cases of congestive heart failure (CHF). The most likely common cause is chronic kidney insufficiency (CKI), which is present in about half of all CHF cases. The CKI is likely to be due to the renal vasoconstriction that often accompanies CHF and can cause long-standing renal ischemia. This reduces the amount of erythropoietin (EPO) produced in the kidney and leads to anemia. However, anemia can occur in CHF without CKI and is likely to be due to excessive cytokine production (for example, tumor necrosis factor-alfa (TNF-alfa) and interleukin-6 (IL-6)), which is common in CHF and can cause reduced EPO secretion, interference with EPO activity in the bone marrow and reduced iron supply to the bone marrow. 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 (LVH), which can lead to cardiac cell death through apoptosis and worsen the CHF. Therefore, a vicious circle 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. We have termed this vicious circle the cardio renal anemia (CRA) syndrome. Patients with CHF who are anemic are often resistant to all CHF medications resulting in being hospitalized repeatedly. Many studies also demonstrate that these patients die more rapidly than their non-anemic counterparts do. In addition, they have a more rapid deterioration in their renal function and can end up on dialysis. There is now evidence from both uncontrolled and controlled studies that early correction of the CHF anemia with subcutaneous EPO and intravenous (i.v.) iron improves shortness of breath and fatigue, cardiac function, renal function and exercise capability, dramatically reducing the need for hospitalization. For these reasons, it is not surprising that quality of life has also been shown to improve. As both CHF and end-stage renal disease (ESRD) are rapidly increasing, the possibility that these twin conditions can be improved by the adequate treatment of anemia offers new hope for slowing the progression of both conditions.
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PMID:The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? 1559 47

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

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP-1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.
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PMID:Growth factor treatment of stroke. 1585 97

Neonatal stroke is a condition that leads to disability in later life, and as yet there is no effective treatment. Recently, erythropoietin (EPO) has been shown to be cytoprotective following brain injury and may promote neurogenesis. However, the effect of EPO on functional outcome and on morphologic changes in neonatal subventricular zone (SVZ) following experimental neonatal stroke has not been described. We used a transient focal model of neonatal stroke in P10 rat. Injury was documented by diffusion weighted MRI during occlusion. Immediately upon reperfusion, either EPO (5U/gm) or vehicle was administered intraperitoneally and animals were allowed to grow for 2 wk. Sensorimotor function was assessed using the cylinder rearing test and then brains were processed for volumetric analysis of the SVZ. Stroke induced SVZ expansion proportional to hemispheric volume loss. EPO treatment markedly preserved hemispheric volume and decreased the expansion of SVZ unilaterally. Furthermore, EPO treatment significantly improved the asymmetry of forelimb use following neonatal stroke. This functional improvement directly correlated with the amount of preserved hemispheric volume. These results suggest EPO may be a candidate in the treatment of neonatal stroke.
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PMID:Erythropoietin improves functional and histological outcome in neonatal stroke. 1587 87


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