Zheng Binbin, Ye Libing, Zhou Yulong, Zhu Sipin, Wang Qingqing, Shi Hongxue, Chen Daqing, Wei Xiaojie, Wang Zhouguang, Li Xiaokun, Xiao Jian, Xu Huazi, Zhang Hongyu
Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Cell Mol Med. 2016 Jun;20(6):1062-75. doi: 10.1111/jcmm.12761. Epub 2016 Jan 15.
After spinal cord injury (SCI), disruption of blood-spinal cord barrier (BSCB) elicits blood cell infiltration such as neutrophils and macrophages, contributing to permanent neurological disability. Previous studies show that epidermal growth factor (EGF) produces potent neuroprotective effects in SCI models. However, little is known that whether EGF contributes to the integrity of BSCB. The present study is performed to explore the mechanism of BSCB permeability changes which are induced by EGF treatment after SCI in rats. In this study, we demonstrate that EGF administration inhibits the disruption of BSCB permeability and improves the locomotor activity in SCI model rats. Inhibition of the PI3K/Akt pathways by a specific inhibitor, LY294002, suppresses EGF-induced Rac1 activation as well as tight junction (TJ) and adherens junction (AJ) expression. Furthermore, the protective effect of EGF on BSCB is related to the activation of Rac1 both in vivo and in vitro. Blockade of Rac1 activation with Rac1 siRNA downregulates EGF-induced TJ and AJ proteins expression in endothelial cells. Taken together, our results indicate that EGF treatment preserves BSCB integrity and improves functional recovery after SCI via PI3K-Akt-Rac1 signalling pathway.
脊髓损伤（SCI）后，血脊髓屏障（BSCB）的破坏引发中性粒细胞和巨噬细胞等血细胞浸润，导致永久性神经功能障碍。先前的研究表明，表皮生长因子（EGF）在SCI模型中具有强大的神经保护作用。然而，关于EGF是否有助于维持BSCB的完整性却知之甚少。本研究旨在探讨大鼠SCI后EGF治疗引起的BSCB通透性变化的机制。在本研究中，我们证明给予EGF可抑制BSCB通透性的破坏，并改善SCI模型大鼠的运动活性。用特异性抑制剂LY294002抑制PI3K/Akt通路，可抑制EGF诱导的Rac1激活以及紧密连接（TJ）和黏附连接（AJ）的表达。此外，EGF对BSCB的保护作用在体内和体外均与Rac1的激活有关。用Rac1 siRNA阻断Rac1激活可下调EGF诱导的内皮细胞TJ和AJ蛋白表达。综上所述，我们的结果表明，EGF治疗通过PI3K-Akt-Rac1信号通路维持BSCB的完整性，并改善SCI后的功能恢复。
