Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex.
Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex.
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DOI：
10.1111/jnc.14281
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发表时间：
2018-04
影响因子：
4.7
通讯作者：
Prado MAM
中科院分区：
文献类型：
--
作者：
Beraldo FH;Ostapchenko VG;Xu JZ;Di Guglielmo GM;Fan J;Nicholls PJ;Caron MG;Prado VF;Prado MAM
应激诱导磷蛋白1（STI 1）作为缺血性脑中的神经保护因子，其水平在缺血后增加。以前的工作表明，在中风模型中，这些STI 1的作用依赖于骨髓源性干细胞的募集，以改善缺血性损伤后的结果。然而，STI 1可以通过与细胞朊蛋白（PrPC）结合并激活α7烟碱乙酰胆碱受体（α 7 nAChR）来直接增加神经元中的神经保护信号。鉴于α 7 nAChR激活也参与了卒中的神经保护，STI 1可能对神经元具有直接作用，以防止缺血性损伤的有害后果。在这里，我们测试了这一假设，暴露原代神经元培养1小时的氧-葡萄糖剥夺（OGD）和再灌注和评估信号通路激活STI 1/PrPC。我们的研究结果表明，STI 1处理显著减少了OGD小鼠神经元的凋亡和细胞死亡，其方式依赖于PrPC和α 7 nAChR，但也依赖于激活素A受体1（ALK 2），后者已成为STI 1的信号伴侣。有趣的是，ALK 2受体的药理学抑制阻止了STI 1的神经保护作用，而骨形态发生蛋白4（BMP 4）在OGD之前或之后激活ALK 2受体可有效减少缺血诱导的神经元死亡。我们的结论是，PrPC/STI 1的参与及其随后的下游信号级联涉及α 7 nAChR以及ALK 2受体可能被激活的神经元中增加的STI 1水平。该信号通路保护神经元免受缺血性损伤。
Stress-inducible phosphoprotein 1 (STI1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI1 actions in a stroke model depend on the recruitment of bone marrow-derived stem cells to improve outcomes after ischemic insult. However, STI1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (PrPC) and activating α7 nicotinic acetylcholine receptors (α7nAChR). Given that α7nAChR activation has also been involved in neuroprotection in stroke, it is possible that STI1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1-h oxygen-glucose deprivation (OGD) and reperfusion and assessing signaling pathways activated by STI1/PrPC. Our results demonstrated that STI1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on PrPC and α7nAChR, but also on the activin A receptor 1 (ALK2), which has emerged as a signaling partner of STI1. Interestingly, pharmacological inhibition of the ALK2 receptor prevented neuroprotection by STI1, while activation of ALK2 receptors by bone morphogenetic protein 4 (BMP4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that PrPC/STI1 engagement and its subsequent downstream signaling cascades involving α7nAChR as well as the ALK2 receptor may be activated in neurons by increased levels of STI1. This signaling pathway protects neurons from ischemic insults.
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影响因子：
1.7
作者：
Bertrand, S;DevillersThiery, A;Bertrand, D
通讯作者：
Bertrand, D
影响因子：
5.3
作者：
Caetano, Fabiana A.;Lopes, Marilene H.;Prado, Marco A. M.
通讯作者：
Prado, Marco A. M.
影响因子：
3.3
作者：
da Fonseca, A. C. C.;Romao, L.;Lima, F. R. S.
通讯作者：
Lima, F. R. S.
影响因子：
5.4
作者：
Hu, JM;Toft, D;Wang, XT
通讯作者：
Wang, XT
影响因子：
4.8
作者：
Kihara, T;Shimohama, S;Akaike, A
通讯作者：
Akaike, A