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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke
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Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke

机译：促红细胞生成素诱导的脑基因表达变化揭示了在实验性卒中中突触可塑性基因的诱导

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摘要

Erythropoietin (EPO) is a neuroprotective cytokine in models of ischemic and nervous system injury, where it reduces neuronal apoptosis and inflammatory cytokines and increases neurogenesis and angiogenesis. EPO also improves cognition in healthy volunteers and schizophrenic patients. We studied the effect of EPO administration on the gene-expression profile in the ischemic cortex of rats after cerebral ischemia at early time points (2 and 6 h). EPO treatment up-regulated genes already increased by ischemia. Hierarchical clustering and analysis of overrepresented functional categories identified genes implicated in synaptic plasticity—Arc BDNF. Egr1. and Egr2, of which Egr2 was the most significantly regulated. Up-regulation of Arc, BDNF, DuspS, Egr1, Egr2, Egr4, and Nr4a3 was confirmed by quantitative PCR. We investigated the up-regulation of Egr2IKrox20 further because of its role in neuronal plasticity. Its elevation by EPO was confirmed in an independent in vivo experiment of cerebral ischemia in rats. Using the rat neuroblastoma B104, we found that wild-type cells that do not express EPO receptor (EPOR) do not respond to EPO by inducing Egr2. However, EPOR-expressing B104 cells induce Egr2 early upon incubation with EPO, indicating that Egr2 induction is a direct effect of EPO and that EPOR mediates this effect. Because these changes occur in vivo before decreased inflammatory cytokines or neuronal apoptosis is evident, these findings provide a molecular mechanism for the neuroreparative effects of cytokines and suggest a mechanism of neuroprotection by which promotion of a plastic phenotype results in decreased inflammation and neuronal death.
机译：促红细胞生成素（EPO）是缺血和神经系统损伤模型中的一种神经保护性细胞因子，可减少神经元凋亡和炎性细胞因子，并增加神经发生和血管生成。 EPO还可以改善健康志愿者和精神分裂症患者的认知。我们研究了在早期时间点（2和6小时），EPO给药对大鼠脑缺血后缺血皮层基因表达谱的影响。 EPO治疗上调的基因已经因缺血而增加。层次聚类和过度代表的功能类别分析确定了与突触可塑性有关的基因Arc BDNF。 Egr1。和Egr2，其中Egr2受最明显的监管。通过定量PCR证实了Arc，BDNF，DuspS，Egr1，Egr2，Egr4和Nr4a3的上调。由于其在神经元可塑性中的作用，我们进一步研究了Egr2IKrox20的上调。在大鼠脑缺血的一项独立体内实验中证实了EPO引起的升高。使用大鼠神经母细胞瘤B104，我们发现不表达EPO受体（EPOR）的野生型细胞不会通过诱导Egr2来响应EPO。但是，表达EPOR的B104细胞在与EPO一起孵育后会早期诱导Egr2，这表明Egr2诱导是EPO的直接作用，而EPOR介导了这种作用。因为这些变化是在炎症细胞因子减少或神经元凋亡明显之前在体内发生的，所以这些发现为细胞因子的神经修复作用提供了分子机制，并提出了神经保护机制，通过这种机制可塑性表型的促进导致炎症减少和神经元死亡。

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    Manuela Mengozzi; Maria Cervellini; Pia Villa; Ziibeyde Erbayraktar; Necati G6kmen; Osman Yilmaz; Serhat Erbayraktar; Mathini Manohasandra; Paul Van Hummelen; Peter Vandenabeele; Yuti Chernajovsky; Alexander Annenkov; Pietro Ghezzi;

  • 作者单位

    Brighton and Sussex Medical School, Falmer, BN19RY, United Kingdom;

    Brighton and Sussex Medical School, Falmer, BN19RY, United Kingdom;

    lstituto Mario Negri, 20157 Milan, Italy,Neuroscience Institute, Consiglio Nazionale delle Ricerche, 20129 Milan, Italy;

    Dokuz Eylul University, izmir 35340, Turkey;

    Dokuz Eylul University, izmir 35340, Turkey;

    Dokuz Eylul University, izmir 35340, Turkey;

    Dokuz Eylul University, izmir 35340, Turkey;

    Brighton and Sussex Medical School, Falmer, BN19RY, United Kingdom;

    MicroArray Facility, Flanders Institute of Biotechnology, 3000 Leuven, Belgium,Department of Medical Oncology, Dana Farber Cancer Institute, Boston MA 02115;

    Department for Molecular Biomedical Research, Flanders Institute of Biotechnology and Ghent University, 9052 Ghent, Belgium,Department of Biomedical Molecular Biology,Ghent University, 9052 Ghent, Belgium;

    Bone and Joint Research Unit, William Harvey Research Institute, Baits and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom;

    Bone and Joint Research Unit, William Harvey Research Institute, Baits and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom;

    Brighton and Sussex Medical School, Falmer, BN19RY, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    microarrays; ischemia-reperfusion injury; neurotrophins; early genes; neuronal cells;

    机译：微阵列缺血再灌注损伤;神经营养蛋白早期基因;神经元细胞;

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