Long-term disability after
stroke is common but the mechanisms of post-
stroke recovery remain unclear. Cerebral Ras-related C3
botulinum toxin substrate (Rac) 1 contributes to functional recovery after
ischemic stroke in mice. As Rac1 plays divergent roles in individual cell types after central neural system injury, we herein examined the specific role of neuronal Rac1 in post-
stroke recovery and axonal regeneration. Young male mice were subjected to 60-min of
middle cerebral artery occlusion (MCAO). Inducible deletion of neuronal Rac1 by daily
intraperitoneal injection of
tamoxifen (2 mg/40 g) into Thy1-creER/Rac1-floxed mice day 7-11 after MCAO worsened cognitive (assayed by novel object recognition test) and sensorimotor (assayed by adhesive removal and pellet reaching tests) recovery day 14-28 accompanied with the reduction of neurofilament-L (NFL) and
myelin basic protein (MBP) and the elevation of
glial fibrillary acidic protein (GFAP) in the peri-
infarct zone assessed by immunostaining. Whereas the brain tissue loss was not altered assayed by
cresyl violet staining. In another approach, delayed overexpression of neuronal Rac1 by injection of lentivirus encoding Rac1 with neuronal promotor into both the cortex and striatum (total 4 μl at 1 × 109 transducing units/mL) of
stroke side in C57BL/6J mice day 7 promoted
stroke outcome, NFL and MBP regrowth and alleviated GFAP invasion. Furthermore, neuronal Rac1 over-expression led to the activation of p21 activating
kinases (PAK) 1,
mitogen-activated protein kinase kinase (
MEK) 1/2 and
extracellular signal-regulated kinase (ERK) 1/2, and the elevation of
brain-derived neurotrophic factor (
BDNF) day 14 after
stroke. Finally, we observed higher counts of neuronal Rac1 in the peri-
infarct zone of subacute/old
ischemic stroke subjects. This work identified a neuronal Rac1 signaling in improving functional recovery and axonal regeneration after
stroke, suggesting a potential therapeutic target in the recovery stage of
stroke.