Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke
- 29 May 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (24), 9617-9622
- https://doi.org/10.1073/pnas.1200554109
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
This publication has 52 references indexed in Scilit:
- Erythropoietin: not just about erythropoiesisThe Lancet, 2010
- Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK PathwayJournal of Biological Chemistry, 2008
- Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemiaNeuroscience Research, 2007
- Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitisJournal of Neuroimmunology, 2006
- Microarray data analysis: from disarray to consolidation and consensusNature Reviews Genetics, 2006
- Erythropoietin treatment improves neurological functional recovery in EAE miceBrain Research, 2005
- Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptorProceedings of the National Academy of Sciences, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stressProceedings of the National Academy of Sciences, 2001
- Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long-term enhancementJournal of Neuroscience, 1993