Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury.
Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury.
复制标题
视黄酸诱导的自噬流抑制内质网应激依赖性细胞凋亡并防止脊髓损伤后血脊髓屏障的破坏
DOI：
10.7150/ijbs.13229
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发表时间：
2016
影响因子：
9.2
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Zhou Y;Zhang H;Zheng B;Ye L;Zhu S;Johnson NR;Wang Z;Wei X;Chen D;Cao G;Fu X;Li X;Xu HZ;Xiao J
脊髓损伤（SCI）引起血-脊髓屏障（BSCB）的破坏，这导致血细胞浸润、炎症反应和神经元细胞死亡，从而导致脊髓继发性损伤。维甲酸（RA）在缺血性脑损伤和脊髓损伤中均具有神经保护作用，但SCI中BSCB破坏与RA的关系尚不清楚。在这项研究中，我们证明了自噬和ER应激参与了RA对BSCB的保护作用。在体内以及在脑微血管内皮细胞（BMEC）中，RA减弱BSCB通透性，并减少损伤后紧密连接（TJ）分子如P120、β-catenin、Occludin和Claudin 5的丢失。此外，RA给药改善了SCI大鼠模型的功能恢复。RA通过诱导自噬流抑制CHOP和caspase-12的表达。RA对GRP 78和PDI蛋白表达无明显影响。此外，结合RA与自噬抑制剂氯喹（CQ）部分取消其对BSCB的保护作用，通过加剧ER应激和随后的紧密连接的损失。总之，RA在SCI恢复中的神经保护作用与通过激活自噬流和抑制ER应激诱导的细胞凋亡来预防BSCB破坏有关。这些发现为RA在中枢神经系统疾病，特别是与BSCB破坏相关的疾病中的未来转化研究奠定了基础。
Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) which leads to infiltration of blood cells, an inflammatory response, and neuronal cell death, resulting spinal cord secondary damage. Retinoic acid (RA) has a neuroprotective effect in both ischemic brain injury and SCI, however the relationship between BSCB disruption and RA in SCI is still unclear. In this study, we demonstrated that autophagy and ER stress are involved in the protective effect of RA on the BSCB. RA attenuated BSCB permeability and decreased the loss of tight junction (TJ) molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in Brain Microvascular Endothelial Cells (BMECs). Moreover, RA administration improved functional recovery in the rat model of SCI. RA inhibited the expression of CHOP and caspase-12 by induction of autophagic flux. However, RA had no significant effect on protein expression of GRP78 and PDI. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB via exacerbated ER stress and subsequent loss of tight junctions. Taken together, the neuroprotective role of RA in recovery from SCI is related to prevention of of BSCB disruption via the activation of autophagic flux and the inhibition of ER stress-induced cell apoptosis. These findings lay the groundwork for future translational studies of RA for CNS diseases, especially those related to BSCB disruption.