Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways
Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways
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DOI：
10.1096/fj.05-3941fje
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发表时间：
2005-10-01
期刊：
影响因子：
4.8
通讯作者：
Hermann, DM
中科院分区：
文献类型：
--
作者：
Kilic, E;Kilic, Ü;Hermann, DM
除了造血功能外，促红细胞生成素（Epo）在脑缺氧和缺血时还具有神经保护功能。为了研究Epo在体内神经保护作用的机制，我们使用了tg21转基因小鼠系，该小鼠系在大脑中组成性地表达人Epo，而不诱导过度红细胞增生。我们发现人类Epo在tg21大脑中表达，皮质和纹状体神经元携带Epo受体。大脑中动脉闭塞后，无论是重度（90 min）缺血还是轻度（30 min）缺血，人Epo都能有效保护tg21小鼠的大脑免受缺血损伤。组织化学研究表明，Epo诱导了缺血脑中JAK-2、ERK-1/-2和Akt通路的激活。这种激活与神经元中Bcl-X-L升高和NO合成酶-1和-2水平降低有关。脑室内注射ERK-1/-2 （PD98059）或Akt （wortmannin）通路的选择性抑制剂表明，Epo的神经保护功能需要ERK-1/-2和Akt，拮抗任何一条通路都完全取消组织保护。另一方面，阻断ERK-1/ 2和Akt并没有逆转神经元NO合成酶-1/-2的抑制，这表明Epo以ERK-1/-2和Akt独立的方式下调了这些NO合成酶。根据我们的数据，ERK-1/ 2和Akt的双重激活对Epo的神经保护活性至关重要。
Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective functions in brain hypoxia and ischemia. To examine the mechanisms mediating Epo's neuroprotective activity in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo in brain without inducing excessive erythrocytosis. We show that human Epo is expressed in tg21 brains and that cortical and striatal neurons carry the Epo receptor. After middle cerebral artery occlusion, human Epo potently protected brains of tg21 mice against ischemic injury, both when severe (90 min) and mild (30 min) ischemia was imposed. Histochemical studies revealed that Epo induced an activation of JAK-2, ERK-1/-2, and Akt pathways in the ischemic brain. This activation was associated with elevated Bcl-X-L and decreased NO synthase-1 and -2 levels in neurons. Intracerebroventricular injections of selective inhibitors of ERK-1/-2 (PD98059) or Akt (wortmannin) pathways revealed that both ERK-1/-2 and Akt were required for Epo's neuroprotective function, antagonization of either pathway completely abolishing tissue protection. On the other hand, ERK-1/-2 and Akt blockade did not reverse the neuronal NO synthase-1/-2 inhibition, indicating that Epo down-regulates these NO synthases in an ERK-1/-2 and Akt independent manner. On the basis of our data, the dual activation of ERK-1/-2 and Akt is crucial for Epo's neuroprotective activity.