Objective To investigate the effects of recombinant human erythropoietin(rh-EPO) on neurobehavioral development and peripheral monocyte interleukin-17(IL-17) and interleukin-23(IL-23) expression in infants with premature anemia. Methods A total of 64 cases of anemia premature infants were randomly assigned to the treatment group and the control group (32 infants in each group).The control group were given routine treatment, on the basis of treatment,iron was given 10 days after birth. The treatment group was given subcutaneous injection of rh-EPO on the besides the treatment of control group.Treatment time was 5 weeks. The neonatal behavioral neurological assessment (NBNA) was performed before and 4 weeks after treatment in both groups.The Gesell developmental schedules was assessed 12 weeks after treatment. The levels of IL-17 mRNA and IL-23 mRNA in peripheral blood of the two groups were also measured. Results The NBNA scores of the treatment group and the control group at 4 weeks after treatment were higher than the pre-treatment,and the difference was statistically significant(P<0.05).The NBNA score of the treatment group was higher than that of the control group at 4 weeks after treatment(P<0.05). The Gesell's assessment showed that the gross weight,fine motor,adaptive behavior,language,and individual-social behavior scores of the treatment group were higher than those of the control group(P<0.05).The relative expressions of IL-17 mRNA and IL-23 mRNA in the treatment group and the control group were lower than those before treatment at 4 weeks after treatment,and the difference was statistically significant(P<0.05).The levels of IL-17 mRNA and IL-23 mRNA were measured in the treatment group 4 weeks after treatment.The relative expression levels were lower than the control group,and the difference was statistically significant(P<0.05). Conclusion rh-EPO contributes to the development of neurobehavior in premature infants with anemia,and has a protective effect on brain injury,which can reduce the expression of IL-17 and IL-23 proinflammatory cytokines.
促红细胞生成素(erythropoietin,EPO)是一种主要是由肾脏和肝脏分泌的活性糖蛋白,可以通过与红细胞上特异性EPO受体结合,从而促进红细胞增殖、分化、成熟[1,2]。重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)具有促进红系造血祖细胞的分化、促进红细胞生成的作用,还是一种神经营养因子,可改善由多种原因所导致的脑损伤,可改善脑损伤导致的认知学习损害、神经行为发育障碍[3]。对于临床早产儿贫血情况以往通常多采用补充铁剂治疗,但随着医学技术的进步,rh-EPO已成为治疗新生儿贫血的新方法。目前国内外研究中rh-EPO对于外周血单核细胞IL-17和IL-23的表达影响的研究较少,因此,2015年7月—2017年9月本研究通过对rh-EPO治疗后的患儿的外周血单核细胞IL-17和IL-23表达的变化,来探究其关联性,报道如下。
GARGB,SHARMAD,BANSALA.Systematic review seeking erythropoietin role for neuroprotection in neonates with hypoxic ischemic encephalopathy:presently where do we stand[J].,2018,31(23):3214-3224.
Abstract BACKGROUND: Hypoxic ischemic encephalopathy (HIE) is one of the leading causes of neonatal mortality in developing countries and leads to some form of neuro-developmental disability in latter part of life. AIMS: The aim of this study is to evaluate the role of erythropoietin (EPO) in neuroprotection for term newborn having HIE. METHOD: The literature search was done for various trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of science, Scopus, Index Copernicus, and other database. RESULTS: A total of nine studies fulfilled inclusion criteria. EPO has shown to cause reduction in death and disability, better long-term neuro-developmental outcome, improvement in EEG, and reduction in risk of cerebral palsy. CONCLUSION: EPO treatment has neuroprotective effects against moderate/severe HIE and improves long-term behavioral neurological developments in neonates.
AWOGUA U,ABOHWEYEREA E.Alpha erythropoietin in the management of anaemia of prematurity:a report of three cases in Nigeria[J].,2006,13(4):361-365.
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MATSUYAMAT,TANAKAT,TATSUMIK,et al.Midazo-lam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system[J].,2015,76(11):89-98.
Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1 and HIF-2 proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.
YUANR,WANGB,LUW,et al.A distinct region in erythropoietin that induces immuno/inflammatory modulation and tissue protection[J].,2015,12(4):850-861.
Beneficial effects of short-term whole-molecule erythropoietin (EPO) therapy have been demonstrated on several animal models of diverse central nervous system pathology. However, the increased hematocrit induced by EPO-driven marrow stimulation greatly limits its potential for side effect-free therapy. We created a library of EPO-derived fragments based on the hypothesis that 2 distinct functions, erythropoiesis and tissue protection, reside in different regions of the molecule. Several small EPO-derived peptides within the A loop of whole EPO molecule were screened for tissue protection in EAE mice. The 19-mer JM-4 peptide that contains 2 cysteine molecules consistently demonstrated the most potent clinical beneficial effects without producing hematocrit alterations in animal models of EAE. The JM-4-induced tissue protection was associated with modulation of the immunoregulatory process that drives inflammation and provokes subsequent autoimmune damage. Like the whole EPO molecule, JM-4 effectively modulated immune/inflammatory reaction within both the peripheral lymphatic tissue and central nervous system. The major effects induced by JM-4 include blocked expansion of monocyte/dendritic antigen presenting cell and T helper 17 cell populations, decreased proinflammatory cytokine production, and sharply enhanced expansion of the regulatory T-cell population. JM-4 shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation.
NAGAYAY,AOYAMAT,TAMURAT,et al.Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α[J].,2014,40(11):3620-3626.
Abstract Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood–brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo . In cultured astrocytes exposed to hypoxic conditions for 6 and 1202h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response.
RANGARAJANV,JUULS E.Erythropoietin:emerging role oferythropoietin in neonatal neuroprotectionⅢ[J].,2014,51(4):481-488.
In the last two decades, there has been considerable evolution in understanding the role of erythropoietin in neuroprotection. Erythropoietin has both paracrine and autocrine functions in the brain. Erythropoietin binding results in neurogenesis, oligodendrogenesis, and angiogenesis. Erythropoietin and its receptor are upregulated by exposure to hypoxia and proinflammatory cytokines after brain injury. While erythropoietin aids in recovery of locally injured neuronal cells, it provides negative feedback to glial cells in the penumbra, thereby limiting extension of injury. This forms the rationale for use of recombinant erythropoietin and erythropoietin mimetics in neonatal and adult injury models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage, and neonatal hypoxic ischemia. Review of published literature (Pubmed, Medline, and Google scholar). Preclinical neuroprotective data are reviewed, and the rationale for proceeding to clinical trials is discussed. Results from phase I/II trials are presented, as are updates on ongoing and upcoming clinical trials of erythropoietin neuroprotection in neonatal populations. The scientific rationale and preclinical data for erythropoietin neuroprotection are promising. Phase II and III clinical trials are currently in process to determine the safety and efficacy of neuroprotective dosing of erythropoietin for extreme prematurity and hypoxic-ischemic encephalopathy in neonates.
ROBERTSONC S,YAMALJ M,TILLEYB C.Erythro-poietin for traumatic brain injury-reply[J].,2014,312(18):1928-1929.
Most of the evidence to date supporting neuroprotection after traumatic brain injury with erythropoietin administration comes from experimental studies. Two case-matched studies in patients with traumatic brain injury and large clinical trials in general trauma patients have found improvements in mortality with erythropoietin treatment.For patients with traumatic brain injury, however, recovery of neurological function long-term is more important than simple survival and none of these previous studies have adequately addressed long-term outcome.
NICHOLA,LITTLEL,FRENCHC.Erythro-poietin for traumatic brain injury[J].,2014,312(18):1928-1929.
Most of the evidence to date supporting neuroprotection after traumatic brain injury with erythropoietin administration comes from experimental studies. Two case-matched studies in patients with traumatic brain injury and large clinical trials in general trauma patients have found improvements in mortality with erythropoietin treatment.For patients with traumatic brain injury, however, recovery of neurological function long-term is more important than simple survival and none of these previous studies have adequately addressed long-term outcome.
FANGA Y,GONZALEZF F,SHELDONR A,et al.Effects of combination therapy using hypothermja and erythropoietin in arat model of neonatal hypoxia-ischemia[J].,2013,73(1):12-17.
BACKGROUND: Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI. METHODS: Rats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied. RESULTS: Differences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects. CONCLUSION: No significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy.
WUY W,GONZALEZF F.Erythropoietin:a novel therapy for hypoxicischaemic encephalopathy?[J].,2015,57(Suppl 3):34-39.
Perinatal hypoxic schaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44 53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE.
Systematic review seeking erythropoietin role for neuroprotection in neonates with hypoxic ischemic encephalopathy:presently where do we stand
1
2018
... 促红细胞生成素(erythropoietin,EPO)是一种主要是由肾脏和肝脏分泌的活性糖蛋白,可以通过与红细胞上特异性EPO受体结合,从而促进红细胞增殖、分化、成熟[1,2].重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)具有促进红系造血祖细胞的分化、促进红细胞生成的作用,还是一种神经营养因子,可改善由多种原因所导致的脑损伤,可改善脑损伤导致的认知学习损害、神经行为发育障碍[3].对于临床早产儿贫血情况以往通常多采用补充铁剂治疗,但随着医学技术的进步,rh-EPO已成为治疗新生儿贫血的新方法.目前国内外研究中rh-EPO对于外周血单核细胞IL-17和IL-23的表达影响的研究较少,因此,2015年7月—2017年9月本研究通过对rh-EPO治疗后的患儿的外周血单核细胞IL-17和IL-23表达的变化,来探究其关联性,报道如下. ...
促红细胞生成素与早产儿脑白质损伤的关系研究
1
2015
... 促红细胞生成素(erythropoietin,EPO)是一种主要是由肾脏和肝脏分泌的活性糖蛋白,可以通过与红细胞上特异性EPO受体结合,从而促进红细胞增殖、分化、成熟[1,2].重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)具有促进红系造血祖细胞的分化、促进红细胞生成的作用,还是一种神经营养因子,可改善由多种原因所导致的脑损伤,可改善脑损伤导致的认知学习损害、神经行为发育障碍[3].对于临床早产儿贫血情况以往通常多采用补充铁剂治疗,但随着医学技术的进步,rh-EPO已成为治疗新生儿贫血的新方法.目前国内外研究中rh-EPO对于外周血单核细胞IL-17和IL-23的表达影响的研究较少,因此,2015年7月—2017年9月本研究通过对rh-EPO治疗后的患儿的外周血单核细胞IL-17和IL-23表达的变化,来探究其关联性,报道如下. ...
促红细胞生成素不同用药时机治疗早产儿贫血的效果研究
1
2017
... 促红细胞生成素(erythropoietin,EPO)是一种主要是由肾脏和肝脏分泌的活性糖蛋白,可以通过与红细胞上特异性EPO受体结合,从而促进红细胞增殖、分化、成熟[1,2].重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)具有促进红系造血祖细胞的分化、促进红细胞生成的作用,还是一种神经营养因子,可改善由多种原因所导致的脑损伤,可改善脑损伤导致的认知学习损害、神经行为发育障碍[3].对于临床早产儿贫血情况以往通常多采用补充铁剂治疗,但随着医学技术的进步,rh-EPO已成为治疗新生儿贫血的新方法.目前国内外研究中rh-EPO对于外周血单核细胞IL-17和IL-23的表达影响的研究较少,因此,2015年7月—2017年9月本研究通过对rh-EPO治疗后的患儿的外周血单核细胞IL-17和IL-23表达的变化,来探究其关联性,报道如下. ...