Wu Mu-Yao, Gao Fan, Yang Xiao-Mei, Qin Xia, Chen Guo-Zhao, Li Di, Dang Bao-Qi, Chen Gang
Department of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
Department of Emergency, The First People's Hospital of Zhangjiagang, Suzhou, China.
Brain Res. 2020 Jan 15;1727:146553. doi: 10.1016/j.brainres.2019.146553. Epub 2019 Nov 14.
The mechanisms of secondary brain injury after traumatic brain injury (TBI) are complex and are the result of multiple factors. Protecting the blood-brain barrier (BBB) and ameliorating cerebral edema are two key factors for improving the prognosis of TBI patients. The BBB is regulated by the hedgehog pathway through Scube2 and Shh protein. Matrix metalloproteinase-9 (MMP-9) influences the transport system and enzyme system of vascular endothelial cells, possibly via the hedgehog pathway. The present study aimed to investigate the role and mechanism of MMP-9 in TBI via the hedgehog pathway. Eighty male Sprague-Dawley rats were used to establish a murine model of TBI. Subsequently, the effect of SB-3CT-a specific inhibitor of MMP-9-was assessed via Western blotting, real-time PCR, immunofluorescence, apoptotic assays, and neurological scoring. The results showed that, compared with those of the sham-operation group, the mRNA and protein levels of MMP-9 were significantly increased after TBI, while the expressions of Scube2 and Shh were decreased. Application of SB-3CT at 24 h after TBI significantly reduced neuronal apoptosis and BBB permeability, while increasing expressions of Scube2 and Shh. In conclusion, these findings demonstrate an influence of TBI-induced MMP-9 upregulation in the induction of post-traumatic nerve and BBB injury, which may be partially mediated by Scube2 and Shh via the hedgehog pathway.
创伤性脑损伤（TBI）后继发性脑损伤的机制复杂，是多种因素共同作用的结果。保护血脑屏障（BBB）和减轻脑水肿是改善TBI患者预后的两个关键因素。BBB由刺猬信号通路通过Scube2和Shh蛋白进行调节。基质金属蛋白酶-9（MMP-9）可能通过刺猬信号通路影响血管内皮细胞的转运系统和酶系统。本研究旨在探讨MMP-9在TBI中通过刺猬信号通路所起的作用及机制。选用80只雄性Sprague-Dawley大鼠建立TBI小鼠模型。随后，通过蛋白质免疫印迹法、实时荧光定量PCR、免疫荧光法、凋亡检测和神经功能评分评估MMP-9特异性抑制剂SB-3CT的作用效果。结果显示，与假手术组相比，TBI后MMP-9的mRNA和蛋白水平显著升高，而Scube2和Shh的表达降低。TBI后24小时应用SB-3CT可显著减少神经元凋亡和BBB通透性，同时增加Scube2和Shh的表达。总之，这些研究结果表明TBI诱导的MMP-9上调对创伤后神经和BBB损伤的诱导有影响，这可能部分由Scube2和Shh通过刺猬信号通路介导。
