Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human recombinant Erythropoietin (rHuEpo) has recently been shown to be a potent protector of ischemia- reperfusion injury in warm-liver ischemia. Significant enhancement of hepatic regeneration and survival after large volume partial hepatic resection has also been demonstrated. It was the aim of this study to evaluate the capacities of rHuEpo in the setting of rat liver transplantation. One-hundred-and-twenty Wistar rats were used: 60 recipients received liver transplantation following donor organ treatment (60 donors) with either 1000 IU rHuEpo or saline injection (controls) into portal veins (cold ischemia 18 h, University of Wisconsin (UW) solution). Recipients were allocated to two groups, which either received 1000 IU rHuEpo at reperfusion or an equal amount of saline (control). Animals were sacrificed at defined time-points (2, 4.5, 24, 48 h and 7 days postoperatively) for analysis of liver enzymes, histology [hematoxylin-eosin (HE) staining, periodic acid Schiff staining (PAS)], immunostaining [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Hypoxyprobe] and real-time polymerase chain reaction (RT-PCR) of cytokine mRNA (IL-1, IL-6). Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) values were significantly reduced among the epo-treated animals 24 and 48 h after liver transplantation (LT). The TUNEL and Hypoxyprobe analyses as well as necrotic index evaluation displayed significant reduction of apoptosis and necrosis in rHuEpo-treated graft livers. Erythropoietin reduces ischemia-reperfusion injury after orthotopic liver transplantation in rats.
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PMID:Erythropoietin reduces ischemia-reperfusion injury after liver transplantation in rats. 1931 9

Transplantation of adult marrow stromal cells (MSCs) has been developed as a new method of treating severe ischemia diseases by therapeutic angiogenesis. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting MSCs apoptosis. The effect of EPO on the therapeutic potency of MSCs transplantation in a rat model of limb ischemia was investigated in the current study. The results indicate that the combined treatment with MSC transplantation and EPO infusion is superior to MSC transplantation alone in the treatment of limb ischemia. MSCs transplantation and EPO infusion could enhance the angiogenic effect of each other to achieve a better therapeutic effect. This combination therapy may become a more effective approach for ischemia diseases of the limbs.
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PMID:Erythropoietin augments the efficacy of therapeutic angiogenesis induced by allogenic bone marrow stromal cells in a rat model of limb ischemia. 1943 14

During the early post transplant period, the tubular epithelium is the main target of injuries including ischemia reperfusion and toxicity effects from calcineurin inhibitors. Taking into account the tissue protective effects of erythropoietin mediated through its antiapoptotic properties, we tested whether administration of recombinant human erythropoietin protects against acute cyclosporine nephrotoxicity. Four groups of five rats were intraperitoneally treated over 28 days with 100UI/Kg/48h Epoetin beta (15mg/kg/day CsA diluted in olive oil, 100UI/Kg/48h Epoetin beta+15mg/kg/day CsA, or olive oil. Histological changes due to tubular necrosis were evaluated with Masson'Trichrome staining. Apoptotic nuclei in kidneys were detected using the Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) method. Phospho-Akt, Akt, cleaved caspase 3 and non cleaved caspase 3 expression were evaluated using immunblotting. We demonstrate that recombinant human erythropoietin (epoetin beta) improves renal function and protects against acute tubular injury. Our data suggest that this nephroprotective effect is mediated by Akt activation and inhibition of tubular apoptosis. Indeed, western blotting analysis of caspase 3 cleavage and Akt phosphorylation demonstrates that rhEPO activate Akt signaling and inhibits caspase 3 cleavage induced by CsA. TUNEL staining confirms that rhEPO inhibits CsA-induced tubular apoptosis. In conclusion, we describe here a new potential target of recombinant human erythropoietin and our results provide an interesting framework for further nephroprotective therapies based on recombinant human erythropoietin.
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PMID:Antiapoptotic properties of recombinant human erythropoietin protects against tubular cyclosporine toxicity. 1976 21

Erythropoietin (EPO) protects the kidneys from ischemia/reperfusion (I/R) injury; however, the exact signalling mechanisms are not fully understood. The serum and glucocorticoid-regulated kinase 1 (SGK1) is an anti-apoptotic protein kinase regulated through the phosphatidylinositol 3-kinase (PI3-kinase) pathway by cellular stimuli, hormones and growth factors. The objective of the present study was to examine the role of SGK1 in the renoprotective effects of EPO in renal I/R injury. In vitro, cultures of HEK293 cells were exposed to 16h hypoxia. Incubation with EPO at a doses of 400U/ml exerted a protective effect on cell death assessed by LDH release and Annexin V FACS analysis. This was paralleled by up-regulation of SGK1 expression, as well as phosphorylation. Downregulation of SGK1 expression by small interfering RNA technique ameliorated the anti-apoptotic effect of EPO treatment. In an in vivo rat model of unilateral renal I/R injury, rats were treated with 500U/kg EPO 24h prior to ischemia. EPO resulted in less severe tissue injury and ameliorated the elevation in creatinine and urea nitrogen levels 24h after reperfusion. Furthermore, SGK1 expression and phosphorylation were higher in EPO compared to vehicle-treated rats as demonstrated by real-time PCR, Western blot and immunofluorescence technique. We conclude that EPO protects from renal I/R injury and SGK1 might contribute to the mediation of EPO effects under ischemic conditions.
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PMID:Role of serum and glucocorticoid-regulated kinase-1 in the protective effects of erythropoietin during renal ischemia/reperfusion injury. 1996 32

Erythropoietin (EPO), a glycoprotein essential for red blood cell production acts on several non-erythropoietic tissues. The EPO receptor (EPOR) is expressed in a variety of cell types including neurons, endothelial cells, and cardiomyocytes. Recently, a number of reports have indicated that EPO preserves heart function in models of cardiac ischemia-reperfusion (I/R) injury. A diverse range of cellular/physiological processes is modulated by EPO and are thought to play a role in the preservation of heart function. In vivo, reductions in infarct size, apoptosis, oxidative stress, and inflammation have been reported. More recently, increases in angiogenesis and reductions in arrhythmias have been implicated in the cardioprotective effects of EPO. In vitro, EPO reduces apoptosis, oxidative stress, and inflammation. These cardioprotective effects appear to be mediated by a receptor interaction that is distinct from that responsible for EPO's erythropoietic effects. Downstream of receptor interactions, the activation of phosphatidylinositol-3 kinase (PI3-kinase) and Akt appear to mediate many of EPO's cardioprotective effects. However, there is emerging evidence for Akt-independent mechanisms of cardioprotection including the inhibition of glycogen synthase kinase 3beta, as well as the activation of potassium channels, protein kinase C, and protein kinases such as ERK1/2. This review focuses on the effects of EPO in the heart and the molecular mechanisms by which EPO achieves its cardioprotective effects.
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PMID:Molecular basis of cardioprotection by erythropoietin. 2002 46

Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO(2) by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases.
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PMID:The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. 2009 9

Erythropoietin (EPO) has been shown to enhance angiogenesis, but its precise mechanisms of enhancement during ischemia are not fully elucidated. We examined the effect of EPO on blood flow recovery from acute hind-limb ischemia induced by ligation of the femoral artery in male C57Bl/6 mice. The density of microvessels with platelet adhesion in ischemic tissues was assessed by intravital microscopy. Treatment with EPO (100 and 1000 IU/kg, i.p.) restored blood flow in a dose-dependent manner and increased plasma levels of soluble-P-selectin, vascular endothelial growth factor (VEGF), and stromal cell-derived factor (SDF-1). Flow cytometric analysis revealed increased P-selectin expression on platelets in EPO-treated mice compared to PBS-treated mice. Intravital microscopic studies showed that EPO increased density of microvessels with platelet adhesion selectively in the ischemic tissues. Neutralizing antibody against P-selectin reduced the density of microvessels with platelet adhesion enhanced with EPO and impaired blood flow recovery with reductions in VEGF and SDF-1 levels. These results suggest that EPO administration enhances recovery from hind-limb ischemia, and platelet adhesion to the microvessels is a key event to enhance the angiogenesis in the ischemic tissues.
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PMID:Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice. 2013 17

Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to depend on synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analog darbepoetin alfa reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by four-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 min of 4-VO selectively killed more than 90% of CA1 neurons in the dorsal hippocampus. Rats that had sustained a bilateral loss of hippocampal CA1 neurons in this range (4-VO rats) displayed more errors and longer escape latencies in the Barnes maze compared with sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg i.p.) 4 h before behavioral testing decreased deficits in escape latency for 4-VO rats but not sham-operated controls. This improvement in spatial working memory performance was correlated with increased levels of nitric-oxide metabolites in the ventral hippocampus. Systemic administration of the nitric-oxide synthase inhibitor N(G)-nitro-L-nitro-arginine methyl ester reversed the increase in nitric-oxide metabolites and improvements in spatial working memory produced by darbepoetin alfa (5000 U/kg, i.p.) at a dose (10 mg/kg, i.p.) that did not impair the spatial working memory performance of intact rats. Taken together, these findings suggest that darbepoetin alfa reverses pre-existing spatial working memory deficits resulting from transient global ischemia by increasing the activity of nitric-oxide synthase, an enzyme implicated in synaptic plasticity.
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PMID:Nitric-oxide synthase mediates the ability of darbepoetin alfa to attenuate pre-existing spatial working memory deficits in rats subjected to transient global ischemia. 2016 42

There is a need to develop alternative treatment strategies for the 30% of patients with critical leg ischemia (CLI) for whom conventional modes of revascularization fail. The efficacy erythropoietin (EPO) in this regard has been verified in preclinical models. Erythropoietin receptors are expressed in the human skeletal muscle and possibly, upregulated in CLI. Furthermore, EPO induces angiogenesis and prevents apoptosis in the ischemic skeletal muscle. The use of EPO in conjunction with autologous bone marrow cells or gene-induced angiogenesis with vascular endothelial growth factor may be more effective in inducing angiogenesis and protecting the critically ischemic leg than EPO alone. The recently synthesized nonhemopoietic derivatives of EPO (eg, asialo erythropoietin and carbamylated erythropoietin) allow higher doses to be administered to achieve tissue protective effects, without an unwanted increase in hematocrit. This may allow translation of preclinical studies into clinical trials.
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PMID:Review of the role of erythropoietin in critical leg ischemia. 2046 98

Erythropoietin (EPO) has a neuroprotective effect in the animal model of ischemia/hypoxia, but the mechanisms underlying the EPO effect in traumatic brain injury (TBI) are not well understood. This study examined the potential neuroprotective mechanisms of recombinant human EPO (rhEPO) in rats after TBI. Sixty healthy adult male Sprague-Dawley rats were randomly divided into 5 groups: 1000 U/kg rhEPO-treated, 3000 U/kg rhEPO-treated, 5000 U/kg rhEPO-treated, citicoline, and normal saline (control) groups. The TBI model was based on the modified Feeney's free falling model. Serum samples were collected at 6 hours, 24 hours, 3 days, 5 days, and 7 days after trauma. The serum S100B protein and interleukin-6 (IL-6) levels were measured after treatment in each group with double antibody sandwich enzyme-linked immunosorbent assay. Both serum S100B protein and IL-6 levels were significantly lower in 3000 U/kg rhEPO-treated and 5000 U/kg rhEPO-treated groups (p < 0.001). The decrease in serum S100B protein level was correlated with the dosage of rhEPO. Medium doses of rhEPO achieved the optimum decreases in the serum IL-6 level. Therefore, inhibition of the composition and secretion of S100B protein and IL-6 levels by EPO might be one of the mechanisms involved in decreasing inflammatory reaction in the brain, and may be responsible for the neuroprotective effect after TBI.
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PMID:Effect of recombinant human erythropoietin on serum S100B protein and interleukin-6 levels after traumatic brain injury in the rat. 2050 89


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