中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (8): 1460-1466.doi: 10.4103/1673-5374.303034

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

丰富环境联合法舒地尔抑制海马CA1区神经元死亡减轻记忆障碍

  

  • 出版日期:2021-08-15 发布日期:2021-01-13
  • 基金资助:

    国家自然科学基金面上项目(8167224281972141);上海市重点临床专业(shslczdzk02702);上海市高层次人才专项支持计划杨帆基金(20YF1403500

Environmental enrichment combined with fasudil treatment inhibits neuronal death in the hippocampal CA1 region and ameliorates memory deficits

Gao-Jing Xu1, #, Qun Zhang1, #, Si-Yue Li1, Yi-Tong Zhu1, Ke-Wei Yu1, Chuan-Jie Wang2, Hong-Yu Xie1, *, Yi Wu1, *   

  1. 1Department of rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Rehabilitation Medicine, Jinshan Hospital of Fudan University, Shanghai, China
  • Online:2021-08-15 Published:2021-01-13
  • Contact: Yi Wu, PhD, 16111220064@fudan.edu.cn; Hong-Yu Xie, PhD, xiehongyu@alu.fudan.edu.cn.
  • Supported by:
    The study was financially supported by the National Natural Science Foundation of China, Nos. 81672242, 81972141 (both to YW); Shanghai Municipal Key Clinical Specialty of China, No. shslczdzk02702 (to YW); and Shanghai Special Support Plan for High-Level Talents, Yang Fan Funds of China, No. 20YF1403500 (to QZ). 

摘要:

目前还没有针对脑卒中后认知障碍恢复的特异性疗法。研究显示肌动蛋白细胞骨架调节功能异常与脑卒中后认知功能下降有关,而其重组需要调节ROCK蛋白。法舒地尔可通过抑制ROCK的活化,保护神经元免受细胞骨架破坏损伤,且丰富环境可减轻脑卒中后认知障碍。但两者联合使用的效果尚未可知。实验在6周龄雄性C57/BL6小鼠中建立了光栓塞脑卒中模型,使用法舒地尔在脑卒中后24h起连续14d腹腔注射(10mg/kg,1次/d)和/或连续21d行丰富环境干预。结果发现脑卒中小鼠经丰富环境联合法舒地尔干预后,其海马CA1区神经元数量明显增加,海马中p-cofilin的表达和比例减少,海马CA1区的F-肌动蛋白分布明显增加,尾部悬吊测试以及被动回避测试表现明显改善。提示丰富环境联合法舒地尔可通过抑制海马ROCK/cofilin通路,改变肌动蛋白动力分布,抑制海马CA1区神经元死亡,从而减轻脑卒中后记忆功能障碍,且其效果比单独使用丰富环境或法舒地尔干预更佳。实验于2019年2月20日经复旦大学动物伦理委员会批准,批准号:2019-huashan hospital JS-139。

https://orcid.org/0000-0001-7801-0290 (Gao-Jing Xu); 

https://orcid.org/0000-0003-3813-3709 (Yi Wu)

关键词: 脑卒中, 认知, 环境, 海马, 损伤, 修复, 通路, 神经保护

Abstract: 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. 

Key words: cognitive, environment, hippocampus, injury, neuroprotection, pathway, repair, stroke