Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral involvement during malaria is a complication that leads to seizure, coma, and death. The effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. Erythropoietin (EPO) is one of the more promising drugs in this area. We measured the effect of EPO on the survival of mice infected with Plasmodium berghei ANKA and demonstrated that inoculations of recombinant human EPO at the beginning of the clinical manifestations of cerebral malaria protect >90% of mice from death. This drug has no effect on the course of parasitemia. The effect of EPO was not related to either the inhibition of apoptosis in the brain or the regulation of the increase and decrease of nitric oxide production in the brain and blood, respectively. Tumor necrosis factor-alpha and interferon-gamma mRNA overexpression was inhibited by EPO, and treated mice had fewer brain hemorrhages. EPO has been used in patients with chronic diseases for years, and more recently it has been used to treat acute ischemic stroke. The data presented here provide the first evidence indicating that this cytokine could be useful for the symptomatic prevention of mortality during the acute stage of cerebral malaria.
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PMID:Recombinant human erythropoietin prevents the death of mice during cerebral malaria. 1739 15

Two hematopoietic cytokines are currently gaining increasing attention within neurological research. Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have long been known for their ability to induce the proliferation of certain populations of hematopoietic lineage cells. However, it has recently been found that EPO, G-CSF, and their respective receptors are also expressed in the human central nervous system (CNS) and may be an important part of the brain's endogenous system of protection. Both hematopoietic cytokines have been shown to have neuroprotective potential in a variety of animal disease models both in vitro and in vivo, through the inhibition of apoptosis, induction of angiogenesis, exertion of anti-inflammatory and neurotrophic effects, as well as by the enhancement of neurogenesis. EPO and G-CSF have been extensively studied in the context of hematological disorders and have recently been successfully applied in the first clinical trials in stroke patients. Intravenous high-dose EPO therapy was associated with an improvement in the clinical outcome and preclinical studies with intravenous high-dose G-CSF therapy have clearly shown that it has considerable neuroprotective potential in the acute, as well as in the chronic phase of stroke. In this review, the current knowledge of the neuroprotective mechanisms of EPO and G-CSF is summarized with regard to in vitro and in vivo data. Focus is placed on the role of EPO in neurological disease models with an emphasis on its influence on functional outcome. New experimental results are assessed in detail and correlated with the findings of recent clinical studies.
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PMID:Hematopoietic cytokines--on the verge of conquering neurology. 1734 68

Recent studies have suggested that the brain preconditioning could induce tolerance to ischemia in humans. It has been believed that newly synthesized proteins are required for the acquisition of delayed tolerance in the brain and spinal cord. However, the mechanism other than the synthesis of neuroprotective proteins may also play a pivotal role. Preconditioning may reprogram the response to ischemic injury as seen during hibernation. Preconditioning with hyperbaric oxygen, volatile anesthetics, and xenon seems to be the focus of the attention from the standpoint of the clinical setting. Strong neuroprotection by the preconditioning with isoflurane and xenon is reported in animal experiments and may change the traditional idea of neuroprotection by anesthetics. The discovery that erythropoietin exerts neuroprotective properties has opened new therapeutic avenues. Erythropoietin is induced in the brain by hypoxic preconditioning and by the pharmacological preconditioning. In addition, the intravenous administration of erythropoietin has been shown to be safe and beneficial for acute stroke in humans. Therefore, erythropoietin is now one of the most promising neuroprotective agents. The research in the brain and spinal cord preconditioning will contribute to the elucidation of the mechanism of ischemic injury and to the establishment of new therapies for neuroprotection.
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PMID:[Brain and spinal cord preconditioning for the protection against ischemic injury]. 1736 16

Erythropoietin (EPO) is a pleiotropic cytokine with a therapeutic potential that goes well beyond the treatment of anaemia. The study by Wang et al (2007b) examined the protective effects of EPO in a rat model of embolic stroke. The efficacy and haematological side effects of EPO were compared to those of a carbamylated EPO variant (CEPO). Treatment with EPO dose-dependently reduced infarct volume and improved long-term functional outcome. However, an increase in hematocrit was seen even for doses of EPO that did not offer neuroprotection. These data do not suggest the existence of a therapeutic window between effect and side effect for treatment with EPO. Treatment with CEPO was without haematological side effects.
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PMID:Neuroprotection with or without erythropoiesis; sometimes less is more. 1760 58

Erythropoietin (EPO) has been used clinically both as an erythropoietic stimulating agent in the treatment of anemia and as a tissue-protective agent in diverse clinical settings including stroke, multiple sclerosis, acute myocardial infarction and others. However, use of EPO or EPO-analogues leads to simultaneous targeting of both the erythropoietic and tissue-protective properties of EPO, and this strategy has been associated with several problems. Specifically, the benefit of correction of cancer-related anemia can be offset by the tissue-protective effects of EPO, which may lead to stimulation of cancer cell proliferation. Conversely, the benefit of tissue-protection in patients with stroke or myocardial infarction can be offset by adverse effects associated with the erythropoietic effects of EPO such as elevation of red blood cell mass, hypertension and prothrombotic phenomena. The finding that the erythropoietic and tissue-protective properties of EPO are conferred via two distinct receptor systems raises the interesting possibility of discovering novel drugs that selectively stimulate either the erythropoietic or the tissue-protective activities of EPO. This article reviews the current status of the clinical use of EPO and EPO-analogues in the treatment of cancer-related anemia and for tissue protection, outlines the distinct molecular biology of the tissue-protective and erythropoietic effects of EPO and discusses strategies of selective targeting of these activities with the goal of exploiting the full therapeutic potential of EPO.
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PMID:Selective modulation of the erythropoietic and tissue-protective effects of erythropoietin: time to reach the full therapeutic potential of erythropoietin. 1768 68

Neonatal stroke leads to mortality and severe morbidity, but there is no effective treatment currently available. Erythropoietin (EPO) has been shown to promote cytoprotection and neurogenesis and decrease subventricular zone morphologic changes following brain injury. The long-term cellular response to EPO has not been defined, and local changes in cell fate decision may play a role in functional improvement. We performed middle cerebral artery occlusion in P10 rats. EPO treatment (5 U/g i.p.) significantly preserved hemispheric brain volume 6 weeks after injury. Furthermore, EPO increased the percentage of newly generated neurons while decreasing newly generated astrocytes following brain injury, without demonstrating long-term differences in the subventricular zone. These results suggest that EPO may neuroprotect and direct cell fate toward neurogenesis and away from gliogenesis in neonatal stroke.
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PMID:Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. 1776

Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor kappaB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care.
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PMID:Erythropoietin and oxidative stress. 1847 29

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.
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PMID:Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. 1875 92

Global and focal cerebral ischemia is followed by a secondary damage characterized by oxidative stress, excitotoxicity, inflammation and apoptosis. Erythropoietin (EPO) exerts antiapoptotic, anti-inflammatory, antioxidative, angiogenetic and neurotrophic properties. Its potential therapeutic role has been demonstrated in several animal models of cerebral ischemia and also in a clinical trial of ischemic stroke, so it could be considered an ideal compound for neuroprotection in ischemic stroke and in cardiac arrest. Intracerebral hemorrhage (ICH) is the least treatable form of stroke; the mechanisms involved in the secondary brain injury include hematoma mass effect, neuronal apoptosis and necrosis, inflammation. It has been demonstrated in an experimental ICH that EPO intervenes in the inflammatory process, reduces brain water content, hemorrhage volume and hemispheric atrophy, promotes cell survival, preserves cerebral blood flow, has antiapoptotic protective function against oxidative stress and excitotoxic damage. EPO can attenuate acute vasoconstriction and prevent brain ischemic damage in subarachnoid hemorrhage. The neuroprotective function of EPO has been studied also in traumatic brain injury: it reduces the inflammation and improves cognitive and motor deficits. The authors review some of the physiological actions of EPO in the physiopathology of ischemic and hemorrhagic stroke, subarachnoid hemorrhage and brain trauma, and its potential usefulness in the brain injured patient management.
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PMID:The use of erythtropoietin in cerebral diseases. 1860 42

Erythropoietin (EPO) and its receptor (EPOR), essential for erythropoiesis, are expressed in the nervous system. Recombinant human EPO treatment promotes functional outcome after traumatic brain injury (TBI) and stroke, suggesting that the endogenous EPO/EPOR system plays an important role in neuroprotection and neurorestoration. This study was designed to investigate effects of the EPOR on histological and functional outcomes after TBI. Experimental TBI was induced in adult EPOR-null and wild-type mice by controlled cortical impact. Neurological function was assessed using the modified Morris Water Maze and footfault tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry. As compared to the wild-type injured mice, EPOR-null mice did not exhibit higher susceptibility to TBI as exemplified by tissue loss in the cortex, cell loss in the dentate gyrus, impaired spatial learning, angiogenesis and cell proliferation. We observed that less cortical neurogenesis occurred and that sensorimotor function (i.e., footfault) was more impaired in the EPOR-null mice after TBI. Co-accumulation of amyloid precursor protein (axonal injury marker) and calcium was observed in the ipsilateral thalamus in both EPOR-null and wild-type mice after TBI with more calcium deposits present in the wild-type mice. This study demonstrates for the first time that EPOR null in the nervous system aggravates sensorimotor deficits, impairs cortical neurogenesis and reduces thalamic calcium precipitation after TBI.
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PMID:Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. 1865 21


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