Xu Gao-Jing, Zhang Qun, Li Si-Yue, Zhu Yi-Tong, Yu Ke-Wei, Wang Chuan-Jie, Xie Hong-Yu, Wu Yi
Department of rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Department of Rehabilitation Medicine, Jinshan Hospital of Fudan University, Shanghai, China.
Neural Regen Res. 2021 Aug;16(8):1460-1466. doi: 10.4103/1673-5374.303034.
Currently, no specific treatment exists to promote recovery from cognitive impairment after a stroke. Dysfunction of the actin cytoskeleton correlates well with poststroke cognitive declines, and its reorganization requires proper regulation of Rho-associated kinase (ROCK) proteins. Fasudil downregulates ROCK activation and protects neurons against cytoskeleton collapse in the acute phase after stroke. An enriched environment can reduce poststroke cognitive impairment. However, the efficacy of environmental enrichment combined with fasudil treatment remains poorly understood. A photothrombotic stroke model was established in 6-week-old male C57BL/6 mice. Twenty-four hours after modeling, these animals were intraperitoneally administered fasudil (10 mg/kg) once daily for 14 successive days and/or provided with environmental enrichment for 21 successive days. After exposure to environmental enrichment combined with fasudil treatment, the number of neurons in the hippocampal CA1 region increased significantly, the expression and proportion of p-cofilin in the hippocampus decreased, and the distribution of F-actin in the hippocampal CA1 region increased significantly. Furthermore, the performance of mouse stroke models in the tail suspension test and step-through passive avoidance test improved significantly. These findings suggest that environmental enrichment combined with fasudil treatment can ameliorate memory dysfunction through inhibition of the hippocampal ROCK/cofilin pathway, alteration of the dynamic distribution of F-actin, and inhibition of neuronal death in the hippocampal CA1 region. The efficacy of environmental enrichment combined with fasudil treatment was superior to that of fasudil treatment alone. This study was approved by the Animal Ethics Committee of Fudan University of China (approval No. 2019-Huashan Hospital JS-139) on February 20, 2019.
目前，尚无促进中风后认知障碍恢复的特异性治疗方法。肌动蛋白细胞骨架功能障碍与中风后认知功能下降密切相关，其重组需要对Rho相关激酶（ROCK）蛋白进行适当调控。法舒地尔可下调ROCK激活，并在中风后的急性期保护神经元免受细胞骨架塌陷的影响。丰富的环境可减轻中风后的认知障碍。然而，环境富集与法舒地尔联合治疗的疗效仍知之甚少。在6周龄雄性C57BL/6小鼠中建立了光血栓性中风模型。建模后24小时，这些动物连续14天每天腹腔注射法舒地尔（10 mg/kg）和/或连续21天给予丰富环境。在接受环境富集与法舒地尔联合治疗后，海马CA1区的神经元数量显著增加，海马中p-丝切蛋白的表达和比例降低，海马CA1区F-肌动蛋白的分布显著增加。此外，小鼠中风模型在悬尾试验和穿梭箱被动回避试验中的表现显著改善。这些发现表明，环境富集与法舒地尔联合治疗可通过抑制海马ROCK/丝切蛋白通路、改变F-肌动蛋白的动态分布以及抑制海马CA1区神经元死亡来改善记忆功能障碍。环境富集与法舒地尔联合治疗的疗效优于单独使用法舒地尔治疗。本研究于2019年2月20日获得中国复旦大学动物伦理委员会批准（批准号：2019-华山医院JS-139）。
