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Activation of neuronal Ras‐related C3 botulinum toxin substrate 1 (Rac1) improves post‐stroke recovery and axonal plasticity in mice
Author(s) -
Bu Fan,
Munshi Yashasvee,
Furr J Weldon,
Min Jiawei,
Qi Li,
Patrizz Anthony,
Spahr Zachary R.,
Urayama Akihiko,
Kofler Julia K.,
McCullough Louise D.,
Li Jun
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15195
Subject(s) - glial fibrillary acidic protein , myelin basic protein , biology , mapk/erk pathway , kinase , neuroscience , medicine , microbiology and biotechnology , central nervous system , myelin , immunohistochemistry
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 × 10 9 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.