中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (4): 881-886.doi: 10.4103/1673-5374.382256

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

大脑Ras相关C3肉毒杆菌毒素底物1激活可促进老年小鼠缺血性脑卒后的功能恢复

  

  • 出版日期:2024-04-15 发布日期:2023-09-15

Activation of cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

Fan Bu1, 2, Jia-Wei Min1, Md Abdur Razzaque1, Ahmad El Hamamy1, Anthony Patrizz1, Li Qi1, Akihiko Urayama1, Jun Li1, *   

  1. 1Department of Neurology, University of Texas Health Science Center, Houston, TX, USA; 2Department of Neurology & Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
  • Online:2024-04-15 Published:2023-09-15
  • Contact: Jun Li, PhD, Jun.Li.3@uth.tmc.edu.
  • Supported by:
    This work was supported by NIH grants RF1 AG069466 (to JL and LDM), R01 NS099628 (to JL), and AG069466 (to JL and LDM), and by the American Heart Association award 20POST35180172 (to FB).

摘要:

年龄是脑卒中不良预后的独立危险因素。越来越多的证据表明,轴突再生和血管生成是脑卒中后功能恢复的主要脑部可塑性形式,随着年龄的增长而减弱。以往研究表明,Ras相关的C3肉毒杆菌毒素底物(Rac)1可促进脑卒中年轻小鼠的功能恢复。实验进一步探讨了Rac1在脑卒中鼠龄18-22个月的老年小鼠长期功能恢复和大脑可塑性中的作用。结果发现,随着小鼠年龄的增长,Rac1在大脑中的表达下降了。脑卒中后1d注射Rac1慢病毒促进了小鼠认知和感觉运动功能的恢复,其伴随着梗死周围区域的神经元和增殖性内皮细胞的增加。然而,在脑卒中后连续14d腹腔注射Rac1抑制剂NSC23766对Rac1进行药理抑制,使神经元和增殖性内皮细胞减少,脑卒中预后恶化。此外,Rac1抑制剂抑制了p21激活激酶1的激活,降低了脑源性神经营养因子蛋白水平,并增加了脑卒中后第14天伤侧大脑胶质纤维酸性蛋白的蛋白水平。研究深入揭示了老年大脑缺血后可塑性减弱的机制,并确定Rac1是改善老年人脑卒中后功能恢复的潜在干预目标。

https://orcid.org/0000-0002-6392-9533 (Jun Li)

Abstract: Brain functional impairment after stroke is common; however, the molecular mechanisms of post-stroke recovery remain unclear. It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke. Mounting evidence suggests that axonal regeneration and angiogenesis, the major forms of brain plasticity responsible for post-stroke recovery, diminished with advanced age. Previous studies suggest that Ras-related C3 botulinum toxin substrate (Rac) 1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model. Here, we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged (male, 18 to 22 months old C57BL/6J) brain after ischemic stroke. We found that as mice aged, Rac1 expression declined in the brain. Delayed overexpression of Rac1, using lentivirus encoding Rac1 injected day 1 after ischemic stroke, promoted cognitive (assessed using novel object recognition test) and sensorimotor (assessed using adhesive removal tests) recovery on days 14–28. This was accompanied by the increase of neurite and proliferative endothelial cells in the peri-infarct zone assessed by immunostaining. In a reverse approach, pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells. Furthermore, Rac1 inhibition reduced the activation of p21-activated kinase 1, the protein level of brain-derived neurotrophic factor, and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke. Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

Key words: aging, angiogenesis, brain-derived neurotrophic factor (BDNF), cerebral ischemia, cognitive recovery, neurite, Pak1, Rac1, sensorimotor recovery, stroke