Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia
Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia
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DOI：
10.4161/auto.6.3.11261
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发表时间：
2010-04-01
期刊：
影响因子：
13.3
通讯作者：
Balduini, Walter
中科院分区：
文献类型：
--
作者：
Carloni, Silvia;Girelli, Silvia;Balduini, Walter
我们之前已经证明，在缺氧缺血（HI）的新生大鼠中，给予雷帕霉素会增加自噬，减少细胞凋亡，并显着减少脑损伤。 HI 后，当自噬被阻断时，神经元细胞会迅速走向坏死性细胞死亡。本研究旨在评估自噬和磷脂酰肌醇 3 激酶 (PI3K)/Akt 激酶途径激活在雷帕霉素神经保护作用中的潜在作用。根据病变侧单丹磺酰尸胺 (MDC) 标记，雷帕霉素给药导致 70 kDa S6 激酶 (p70S6K) 磷酸化显着减少，自噬蛋白 Beclin 1 和微管相关蛋白 1 轻链 3 (LC3) 显着增加。神经元细胞中 Akt 和 cAMP 反应元件结合蛋白 (CREB) 的磷酸化增加，p-Akt 和 p-CREB 均与 Beclin 1 共定位。 Wortmannin (WM) 给药显着降低 Akt 和 CREB 磷酸化以及雷帕霉素的神经保护作用，但不影响 p70S6K 的磷酸化和 Beclin 1 的表达 以及 LC3 和 MDC 标记。相反，3-甲基腺嘌呤 (3MA) 减少了 Beclin 1 表达的增加、MDC 标记和雷帕霉素的神经保护作用，而不影响 Akt 磷酸化。然而，这两种化合物均显着增加坏死细胞死亡。综上所述，这些数据表明，在新生儿 HI 中，自噬可能是整合的促生存信号传导的一部分，其中包括 PI3K-Akt-哺乳动物雷帕霉素靶点 (mTOR) 轴。当自噬或 PI3K-Akt-mTOR 途径中断时，细胞会发生坏死性细胞死亡。
We have previously shown that in neonatal rats subjected to hypoxia-ischemia (HI) rapamycin administration increases autophagy, decreases apoptosis and significantly reduces brain damage. After HI, when autophagy is blocked neuronal cells rapidly progress toward necrotic cell death. The present study was undertaken to assess the potential role of activation of autophagic and phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathways in the neuroprotective effect of rapamycin. Rapamycin administration caused a significant reduction of 70 kDa S6 kinase (p70S6K) phosphorylation and a significant increase of the autophagic proteins Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3), as of monodansylcadaverine (MDC) labeling in the lesioned side. The phosphorylation of Akt and cAMP response element binding protein (CREB) was increased in neuronal cells, and both p-Akt and p-CREB colocalized with Beclin 1. Wortmannin (WM) administration significantly reduced Akt and CREB phosphorylation as well as the neuroprotective effect of rapamycin but did not affect the phosphorylation of p70S6K, the expression of Beclin 1 and LC3, and MDC labeling. In contrast, 3-methyladenine (3MA) reduced the increased Beclin 1 expression, the MDC labeling and the neuroprotective effect of rapamycin without affecting Akt phosphorylation. However, both compounds significantly increased necrotic cell death. Taken together, these data indicate that in neonatal HI autophagy can be part of an integrated prosurvival signaling which includes the PI3K-Akt-mammalian target of rapamycin (mTOR) axis. When the autophagic or the PI3K-Akt-mTOR pathways are interrupted cells undergo necrotic cell death.