Gu Chengyao, Wu Yunqin, Fan Zhenyi, Han Weiwei
Department of Neurology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
Department of Rehabilitation, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
Exp Ther Med. 2018 Jan;15(1):377-382. doi: 10.3892/etm.2017.5349. Epub 2017 Oct 23.
The aim was to investigate the neuroprotective effects and potential mechanism mediated by simvastatin in a mouse model of intracerebral hemorrhage. CD-1 mice were subjected to infusion of collagenase type IV into the left striatum in order to induce intracerebral hemorrhage. Western blot analysis, the TUNEL assay and the modified neurological severity score were used in the present study to analyze the efficacy of simvastatin for intracerebral hemorrhage. The results demonstrated that simvastatin treatment improved the cerebral water content and blood-brain barrier disruption in the intracerebral hemorrhage animals. Intracerebral hemorrhage-induced neuronal cell death was downregulated by simvastatin treatment compared with the vehicle-treated model group. In addition, the expression levels of aquaporin-4, matrix metallopeptidase 9 and caspase-3 were downregulated and B-cell lymphoma-2 was upregulated by simvastatin treatment compared with the vehicle-treated model. Simvastatin treatment also significantly reduced the Evans blue leakage into the injured hemispheres and improved motor function. Mechanism analysis further indicated that simvastatin treatment downregulated nuclear factor (NF)-κB expression, and upregulated the myeloid differentiation primary response 88 (MyD88) and TIR domain-containing adaptor protein inducing interferon-β (TRIF) expression levels in neuronal cells in experimental mice. Furthermore, the results revealed that NF-κB overexpression abolished the simvastatin-downregulated MyD88 and TRIF expression levels, as well as the apoptosis of neuronal cells. In conclusion, these results indicated that simvastatin was able to attenuate brain edema and reduce cellular apoptosis by suppressing the NF-κB-mediated MyD88/TRIF signaling pathway subsequent to the induction of intracerebral hemorrhage in mice.
目的是研究辛伐他汀在脑出血小鼠模型中介导的神经保护作用及其潜在机制。将IV型胶原酶注入CD-1小鼠的左纹状体以诱导脑出血。本研究采用蛋白质免疫印迹分析、TUNEL检测和改良神经功能缺损评分来分析辛伐他汀对脑出血的疗效。结果表明，辛伐他汀治疗改善了脑出血动物的脑含水量和血脑屏障破坏情况。与载体处理的模型组相比，辛伐他汀治疗下调了脑出血诱导的神经元细胞死亡。此外，与载体处理的模型相比，辛伐他汀治疗下调了水通道蛋白4、基质金属蛋白酶9和半胱天冬酶3的表达水平，并上调了B细胞淋巴瘤-2的表达。辛伐他汀治疗还显著减少了伊文思蓝向损伤半球的渗漏，并改善了运动功能。机制分析进一步表明，辛伐他汀治疗下调了实验小鼠神经元细胞中核因子（NF）-κB的表达，并上调了髓样分化初级反应蛋白88（MyD88）和含TIR结构域的接头蛋白诱导干扰素-β（TRIF）的表达水平。此外，结果显示NF-κB的过表达消除了辛伐他汀下调的MyD88和TRIF表达水平以及神经元细胞的凋亡。总之，这些结果表明，辛伐他汀能够在小鼠脑出血后通过抑制NF-κB介导的MyD88/TRIF信号通路来减轻脑水肿并减少细胞凋亡。
