Melatonin Enhances Autophagy and Reduces Apoptosis to Promote Locomotor Recovery in Spinal Cord Injury via the PI3K/AKT/mTOR Signaling Pathway
Melatonin Enhances Autophagy and Reduces Apoptosis to Promote Locomotor Recovery in Spinal Cord Injury via the PI3K/AKT/mTOR Signaling Pathway
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DOI：
10.1007/s11064-019-02838-w
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发表时间：
2019-08-01
影响因子：
4.4
通讯作者：
Mei, Xifan
中科院分区：
文献类型：
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作者：
Li, Yuanlong;Guo, Yue;Mei, Xifan
脊髓损伤（SCI）导致神经元死亡，导致中枢神经系统（CNS）功能障碍；然而，其发病机制仍知之甚少。褪黑素 (MT) 是一种主要由松果体分泌的激素，与 SCI 的神经保护作用有关。增强的自噬可以促进SCI后运动功能的恢复并减少细胞凋亡。有趣的是，MT 增加了体内 SCI 中的自噬。然而，MT 增加自噬和减少细胞凋亡的能力，以及对 SCI 后前角运动神经元恢复的潜在影响仍有待阐明。在这项研究中，我们发现 MT 治疗可改善大鼠 SCI 模型的运动功能恢复。事实上，脊髓损伤后，MT 上调了磷脂酰肌醇 3 激酶 (PI3K) 的表达，而蛋白激酶 B (AKT) 和哺乳动物雷帕霉素靶点 (mTOR) 的表达下调。此外，MT 增加了自噬激活蛋白的表达，而 SCI 后神经元中凋亡激活蛋白的表达减少。此外，通过 MT、PI3K 抑制剂 3-甲基腺嘌呤 (3-MA) 和 mTOR 抑制剂雷帕霉素 (Rapa) 治疗，SCI 模型大鼠和脂多糖 (LPS) 刺激的原代神经元的自噬受到抑制，同时诱导细胞凋亡。总的来说，我们的结果表明，MT 可以通过增强自噬以及减少大鼠 SCI 后的细胞凋亡来改善运动功能的恢复，这可能是通过 PI3K/AKT/mTOR 信号通路实现的。
Spinal cord injury (SCI) leads to neuronal death resulting in central nervous system (CNS) dysfunction; however, the pathogenesis is still poorly understood. Melatonin (MT), a hormone secreted mainly by the pineal gland, is associated with neuroprotective effects against SCI. Enhanced autophagy can promote the recovery of locomotor function and reduce apoptosis after SCI. Interestingly, MT increases autophagy in SCI in vivo. Nevertheless, the ability of MT to increase autophagy and decrease apoptosis, and the potential effects on the recovery of motor neurons in the anterior horn after SCI remain to be clarified. In this study, we discovered that MT treatment improved motor function recovery in a rat SCI model. Indeed, MT upregulated the expression of the phosphatidylinositol 3-kinase (PI3K), while expression of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) was downregulated after SCI. Additionally, MT increased the expression of autophagy-activating proteins, while the expression of apoptosis-activating proteins in neurons was decreased following SCI. Furthermore, autophagy was inhibited, while apoptosis was induced in SCI model rats and lipopolysaccharide (LPS)-stimulated primary neurons by treatment with MT, the PI3K inhibitor 3-methyladenine (3-MA) and mTOR inhibitor Rapamycin (Rapa). Collectively, our results suggest that MT can improve the recovery of locomotor function by enhancing autophagy as well as reducing apoptosis after SCI in rats, probably via the PI3K/AKT/mTOR signaling pathway.