Liu Tengyuan, Zhang Tingting, Yu Hemei, Shen Hailian, Xia Weiliang
State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, China.
J Neuroinflammation. 2014 Jun 14;11:107. doi: 10.1186/1742-2094-11-107.
Neuroinflammation mediated by activation of microglia and interruption of the blood-brain barrier (BBB) is an important factor that contributes to neuron death and infarct area diffusion in ischemia reperfusion injury. Finding novel molecules to regulate neuroinflammation is of significant clinical value. We have previously shown that adjudin, a small molecule compound known to possess antispermatogenic function, attenuates microglia activation by suppression of the NF-κB pathway. In this study we continued to explore whether adjudin could be neuroprotective by using the transient middle cerebral artery occlusion (tMCAO) model. Adjudin treatment after reperfusion significantly decreased the infarction volume and neuroscore compared to the vehicle group. Staining of CD11b showed that adjudin markedly inhibited microglial activation in both the cortex and the striatum, accompanied by a reduction in the expression and release of cytokines TNF-α, IL-1β and IL-6. Concomitantly, adjudin noticeably prevented BBB disruption after ischemia and reperfusion, as indicated by the reduction of IgG detection in the brain cortex and striatum versus the vehicle group. This finding was also corroborated by immunofluorescence staining and immunoblotting of tight junction-related proteins ZO-1, JAM-A and Occludin, where the reduction of these proteins could be attenuated by adjudin treatment. Moreover, adjudin obviously inhibited the elevated MMP-9 activity after stroke. Together these data demonstrate that adjudin protects against cerebral ischemia reperfusion injury, and we present an effective neuroinflammation modulator with clinical potential.
由小胶质细胞激活和血脑屏障（BBB）破坏介导的神经炎症是导致缺血再灌注损伤中神经元死亡和梗死面积扩散的重要因素。寻找调节神经炎症的新分子具有重要的临床价值。我们之前已经表明，阿地金，一种已知具有抗生精功能的小分子化合物，通过抑制NF-κB途径减弱小胶质细胞的激活。在本研究中，我们继续使用短暂性大脑中动脉闭塞（tMCAO）模型探索阿地金是否具有神经保护作用。与溶剂对照组相比，再灌注后给予阿地金治疗显著降低了梗死体积和神经评分。CD11b染色显示，阿地金显著抑制了皮质和纹状体中的小胶质细胞激活，同时肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的表达和释放也减少。与此同时，与溶剂对照组相比，大脑皮质和纹状体中IgG检测值的降低表明阿地金显著预防了缺血再灌注后的血脑屏障破坏。紧密连接相关蛋白闭锁小带-1（ZO-1）、连接黏附分子A（JAM-A）和闭合蛋白的免疫荧光染色和免疫印迹也证实了这一发现，阿地金治疗可减弱这些蛋白的减少。此外，阿地金明显抑制了中风后升高的基质金属蛋白酶-9（MMP-9）活性。这些数据共同表明阿地金可保护大脑免受缺血再灌注损伤，我们提出了一种具有临床潜力的有效神经炎症调节剂。
