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Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke

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Abstract
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, Dusp5, Egr1, Egr2, Egr4, and Nr4a3 was confirmed by quantitative PCR. We investigated the up-regulation of Egr2/Krox20 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.
Keywords
microarrays, ischemia-reperfusion injury, neurotrophins, early genes, neuronal cells, RECOMBINANT-HUMAN-ERYTHROPOIETIN, FOCAL CEREBRAL-ISCHEMIA, LONG-TERM POTENTIATION, IMMEDIATE-EARLY GENES, TRANSCRIPTION FACTORS, NEURONAL APOPTOSIS, PROTEIN EXPRESSION, TISSUE PROTECTION, RAT HIPPOCAMPUS, NERVOUS-SYSTEM

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Citation

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Chicago
Mengozzi, Manuela, Ilaria Cervellini, Pia Villa, Zübeyde Erbayraktar, Necati Gökmen, Osman Yilmaz, Serhat Erbayraktar, et al. 2012. “Erythropoietin-induced Changes in Brain Gene Expression Reveal Induction of Synaptic Plasticity Genes in Experimental Stroke.” Proceedings of the National Academy of Sciences of the United States of America 109 (24): 9617–9622.
APA
Mengozzi, M., Cervellini, I., Villa, P., Erbayraktar, Z., Gökmen, N., Yilmaz, O., Erbayraktar, S., et al. (2012). Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109(24), 9617–9622.
Vancouver
1.
Mengozzi M, Cervellini I, Villa P, Erbayraktar Z, Gökmen N, Yilmaz O, et al. Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2012;109(24):9617–22.
MLA
Mengozzi, Manuela, Ilaria Cervellini, Pia Villa, et al. “Erythropoietin-induced Changes in Brain Gene Expression Reveal Induction of Synaptic Plasticity Genes in Experimental Stroke.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109.24 (2012): 9617–9622. Print.
@article{2968132,
  abstract     = {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, Dusp5, Egr1, Egr2, Egr4, and Nr4a3 was confirmed by quantitative PCR. We investigated the up-regulation of Egr2/Krox20 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.},
  author       = {Mengozzi, Manuela and Cervellini, Ilaria and Villa, Pia and Erbayraktar, Z{\"u}beyde and G{\"o}kmen, Necati and Yilmaz, Osman and Erbayraktar, Serhat and Manohasandra, Mathini and Van Hummelen, Paul and Vandenabeele, Peter and Chernajovsky, Yuti and Annenkov, Alexander and Ghezzi, Pietro},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keyword      = {microarrays,ischemia-reperfusion injury,neurotrophins,early genes,neuronal cells,RECOMBINANT-HUMAN-ERYTHROPOIETIN,FOCAL CEREBRAL-ISCHEMIA,LONG-TERM POTENTIATION,IMMEDIATE-EARLY GENES,TRANSCRIPTION FACTORS,NEURONAL APOPTOSIS,PROTEIN EXPRESSION,TISSUE PROTECTION,RAT HIPPOCAMPUS,NERVOUS-SYSTEM},
  language     = {eng},
  number       = {24},
  pages        = {9617--9622},
  title        = {Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke},
  url          = {http://dx.doi.org/10.1073/pnas.1200554109},
  volume       = {109},
  year         = {2012},
}

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