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首页> 外文期刊>Redox Biology >Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice
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Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice

机译：通过PDK-1和PTEN在Thr308上PI3K / Akt的特定磷酸化介导了小鼠局灶性脑缺血后褪黑激素的神经保护活性

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Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonin's neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. However, PI3K/Akt inhibition did not inhibit melatonin's positive effect on brain swelling and IgG extravasation. Additionally, phosphorylation of mTOR, PTEN, AMPKα, PDK1 and RSK1 were increased, while phosphorylation of 4E-BP1, GSK-3α/β, S6 ribosomal protein were decreased in melatonin treated animals. In addition, melatonin decreased apoptosis through reduced p53 phosphorylation by the PI3K/Akt pathway. In conclusion, we demonstrated the activation profiles of PI3K/Akt signaling pathway components in the pathophysiological aspect of ischemic stroke and melatonin's neuroprotective activity. Our data suggest that Akt phosphorylation, preferably at the Thr308 site of the activation loop via PDK1 and PTEN, mediates melatonin's neuroprotective activity and increased Akt phosphorylation leads to reduced apoptosis.
机译：除了其强大的抗氧化性能外，最近的研究还发现褪黑激素可促进小鼠局灶性脑缺血（FCI）后PI3K / Akt磷酸化。但是，尚不清楚（i）PI3K / Akt磷酸化的增加是伴随事件还是直接导致褪黑素的神经保护作用，以及（ii）FCI后褪黑素如何调节PI3K / Akt信号通路。在这项研究中，我们显示，与FacI后褪黑素相比，褪黑素与Ser473相比，Akt在Thr308激活环上被强烈磷酸化。褪黑素治疗可减少梗死体积，这可通过PI3K / Akt抑制作用逆转。但是，PI3K / Akt的抑制并不能抑制褪黑激素对脑肿胀和IgG外渗的积极作用。此外，褪黑激素治疗动物的mTOR，PTEN，AMPKα，PDK1和RSK1的磷酸化增加，而4E-BP1，GSK-3α/β，S6核糖体蛋白的磷酸化减少。另外，褪黑激素通过PI3K / Akt途径通过减少p53磷酸化来减少细胞凋亡。总之，我们在缺血性中风的病理生理方面和褪黑激素的神经保护活性中证明了PI3K / Akt信号通路成分的激活模式。我们的数据表明，Akt磷酸化（最好是通过PDK1和PTEN在激活环的Thr308位点）介导褪黑激素的神经保护活性，而Akt磷酸化的增加导致凋亡减少。

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