Cervical Spinal Erythropoietin Induces Phrenic Motor Facilitation via Extracellular Signal-Regulated Protein Kinase and Akt Signaling
Cervical Spinal Erythropoietin Induces Phrenic Motor Facilitation via Extracellular Signal-Regulated Protein Kinase and Akt Signaling
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DOI：
10.1523/jneurosci.3873-11.2012
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发表时间：
2012-04-25
影响因子：
5.3
通讯作者：
Mitchell, Gordon S.
中科院分区：
文献类型：
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作者：
Dale, Erica A.;Satriotomo, Irawan;Mitchell, Gordon S.
促红细胞生成素(EPO)通常以其在红细胞生成中的作用而闻名，但也是一种对脊髓运动神经元有效的神经营养/神经保护因子。另一种由低氧诱导因子-1调节的营养因子是血管内皮生长因子(VEGF)，它通过ERK和Akt激活信号来诱导长时间的膈运动促进(PMF)。由于EPO也通过ERK和Akt激活来传递信号，我们检验了EPO引起类似PMF的假设。利用逆行标记和免疫组织化学技术，我们在成年、雄性、SD大鼠上证明了EPO及其受体EPO-R在已鉴定的膈运动神经元中表达。鞘内注射C4的EPO可引起持续的PMF；整合的膈神经爆发波幅在注射后90min增加(注射后90min基线的63+/-12%；p<；0.001)。EPO增加了膈运动神经元ERK的磷酸化(和推测的激活)(1.6倍于对照组；p<；0.05)；EPO也增加了pakt(1.6倍于对照组；p<；0.05)。EPO诱导的PMF可被MEK/ERK抑制剂U0126[1，4-diamino-2，3-dicyano-1，4-bis(o-aminophenylmercapto)丁二烯和磷脂酰肌醇3-激酶/Akt抑制剂LY294002[2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one]，阻断，表明ERK MAP和Akt都是EPO诱导PMF所必需的。U0126和LY294002可降低膈运动神经元的PERK和PAKT(p<；0.05)，表明这些激酶之间存在复杂的相互作用。我们的结论是，EPO在呼吸运动控制中引起脊髓可塑性。由于EPO的表达是低氧敏感的，在长期或反复低氧条件下，它可能在呼吸可塑性中发挥作用。
Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by hypoxia-inducible factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Because EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min after injection (63 +/- 12% baseline 90 min after injection; p < 0.001). EPO increased phosphorylation (and presumed activation) of ERK (1.6-fold vs controls; p < 0.05) in phrenic motor neurons; EPO also increased pAkt (1.6-fold vs controls; p < 0.05). EPO-induced pMF was abolished by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene] and the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one], demonstrating that ERK MAP kinases and Akt are both required for EPO-induced pMF. Pretreatment with U0126 and LY294002 decreased both pERK and pAkt in phrenic motor neurons (p < 0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Because EPO expression is hypoxia sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen.