Xueyang Deng, Zhanqiang Ma, Chunhua Ma, Kun Hao
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, PR China.
Central Laboratory, Nanjing Municipal Hospital of T.C.M, The Third Affiliated Hospital of Nanjing University of T.C.M, Nanjing 210001, China.
Oncotarget. 2016 Nov 29;7(48):78764-78772. doi: 10.18632/oncotarget.12853.
The current study was designed to investigate the pathological changes in brain induced by smoke exposure, and explore whether fasudil could alleviate these impairments.Adult C57BL/6 mice were exposed to tobacco smoking for four months, and fasudil was treated from the third months. To investigate lung injuries, the immunohistochemistry of lung tissue, immune cell infiltrations, cytokine productions in bronchoalveolar lavage (BAL) fluid, and seurm inflammatory cytokines were evaluated. To investigate cognitive impairments, Morris water maze test, hippocampal inflammatory cytokines and Rho associated signaling pathways were evaluated.Our findings showed fasudil administration inhibited the inflitration of inflammatory cells (macrophages, neutrophils, and lymphocytes), suppressed the production of inflammatory cytokines both in the BAL fluid, serum, and hippocampus. Further, fasudil significantly improved the spatial learning and memory impairments and reduced the elevation of hippocampal inflammatory cytokines induced by tobacco smoking. Of note, expressions of RhoA, ROCK1, ROCK2, caspase-3, caspase-9, bax and the phosphorylation of NF-κBp65 were increased accompanying the smoke exposure-induced cognitive impairments, which were significantly inhibited by fasudil treatment as indicted in western blot and immunohistochemistry analysis.Our results showed that fasudil exhibited protective effects on smoke exposure induced cognitive deficits which might involve with the regulation of Rho/ROCK/NF-κB pathways. Further studies are warranted before clinical application of fasudil.
本研究旨在探讨烟雾暴露诱导的脑病理变化，并探究法舒地尔是否能减轻这些损伤。将成年C57BL/6小鼠暴露于烟草烟雾中4个月，从第3个月开始给予法舒地尔治疗。为了研究肺损伤，评估了肺组织的免疫组化、免疫细胞浸润、支气管肺泡灌洗（BAL）液中的细胞因子产生以及血清炎症细胞因子。为了研究认知障碍，评估了莫里斯水迷宫试验、海马炎症细胞因子和Rho相关信号通路。我们的研究结果表明，给予法舒地尔可抑制炎症细胞（巨噬细胞、中性粒细胞和淋巴细胞）的浸润，抑制BAL液、血清和海马中炎症细胞因子的产生。此外，法舒地尔显著改善了空间学习和记忆障碍，并降低了吸烟诱导的海马炎症细胞因子的升高。值得注意的是，RhoA、ROCK1、ROCK2、caspase-3、caspase-9、bax的表达以及NF-κBp65的磷酸化在烟雾暴露诱导的认知障碍中增加，如蛋白质免疫印迹和免疫组化分析所示，法舒地尔治疗可显著抑制这些变化。我们的结果表明，法舒地尔对烟雾暴露诱导的认知缺陷具有保护作用，这可能与Rho/ROCK/NF-κB通路的调节有关。在法舒地尔临床应用之前，有必要进行进一步的研究。
