Fingolimod suppresses neuronal autophagy through the mTOR/p70S6K pathway and alleviates ischemic brain damage in mice.
Fingolimod suppresses neuronal autophagy through the mTOR/p70S6K pathway and alleviates ischemic brain damage in mice.
复制标题
DOI：
10.1371/journal.pone.0188748
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Liu JL
中科院分区：
文献类型：
--
作者：
Li X;Wang MH;Qin C;Fan WH;Tian DS;Liu JL
生物活性信号脂质鞘氨醇-1-磷酸（S1P）及其类似物fingolimod （FTY720）先前已显示出对缺血性脑损伤的神经保护作用。然而，其基本机制尚未完全阐明。自噬在缺血性脑卒中中的作用越来越被认识到。在本研究中，我们试图确定S1P通路是否参与脑卒中后神经元自噬并探讨其可能的机制。有趣的是，我们发现FTY720在卒中后第1天和第3天显著降低梗死面积，减少神经元凋亡，并伴有功能缺陷的改善。此外，FTY720被发现以剂量依赖性的方式降低缺血性卒中后自噬体蛋白、微管相关蛋白1轻链3（LC3-II）和Beclin1的诱导。同时，哺乳动物雷帕霉素靶蛋白（mTOR）和70 kda核糖体蛋白S6激酶1 （p70S6K）的蛋白水平也在fty720处理过的动物中上调，而非特异性SphK抑制剂N，N-二甲基sphingosine （DMS）被发现会产生相反的作用。结果表明，FTY720调节S1P信号通路可通过mTOR/p70S6K通路有效减少神经元自噬，减轻小鼠缺血性脑损伤。
The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, fingolimod (FTY720), have previously shown neuroprotective effects against ischemic brain injury. However, the underlying mechanisms have not yet been fully clarified. The roles of autophagy in ischemic stroke are being increasingly recognized. In the present study, we sought to determine whether the S1P pathway is involved in neuronal autophagy and investigate its possible mechanisms following stroke. Interestingly, we found that FTY720 significantly attenuates infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, accompanied by amelioration of functional deficits. Additionally, FTY720 was found to decrease the induction of autophagosome proteins, microtubule-associated protein 1 light chain 3(LC3-II) and Beclin1, following ischemic stroke in a dose-dependent manner. Meanwhile, protein levels of the mammalian target of rapamycin (mTOR) and the 70-kDa ribosomal protein, S6 kinase1 (p70S6K), were also up-regulated in FTY720-treated animals, and the nonspecific SphK inhibitor, N,N-dimethylsphingosine (DMS), was found to cause a reverse effect. Our results indicate that modulation of the S1P signaling pathway by FTY720 could effectively decrease neuronal autophagy through the mTOR/p70S6K pathway and attenuate ischemic brain injury in mice.
登录
查看更多内容
影响因子：
4.6
作者：
Liao, Aijun;Hu, Rong;Liu, Zhuogang
通讯作者：
Liu, Zhuogang
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
4.6
作者：
Moruno Manchon JF;Uzor NE;Dabaghian Y;Furr-Stimming EE;Finkbeiner S;Tsvetkov AS
通讯作者：
Tsvetkov AS
影响因子：
20.1
作者：
Kluk, MJ;Hla, T
通讯作者：
Hla, T