Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (4): 881-886.doi: 10.4103/1673-5374.382256

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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).

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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