Constraint-Induced Movement Therapy Promotes Myelin Remodeling and Motor Function by Mediating Sox2/Fyn Signals in Rats with Hemiplegic Cerebral Palsy

Chaoqiong Fu; Hongmei Tang; Liru Liu; Yuan Huang; Hongyu Zhou; Shiya Huang; Tingting Peng; Peishan Zeng; Xubo Yang; Lu He; Kaishou Xu

doi:10.1093/ptj/pzae011

Constraint-Induced Movement Therapy Promotes Myelin Remodeling and Motor Function by Mediating Sox2/Fyn Signals in Rats with Hemiplegic Cerebral Palsy

Phys Ther. 2024 Feb 1:pzae011. doi: 10.1093/ptj/pzae011. Online ahead of print.

Authors

Chaoqiong Fu^{1

2

3}, Hongmei Tang^{1

2}, Liru Liu^{1

2}, Yuan Huang^{1

2

4}, Hongyu Zhou^{1

2}, Shiya Huang^{1

2

3}, Tingting Peng^{1

2}, Peishan Zeng^{1

2}, Xubo Yang^{1

2}, Lu He^{1

2}, Kaishou Xu^{1

2}

Affiliations

¹ Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China.
² Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China.
³ School of Exercise and Health, Shanghai University of Sport, Shanghai, 10277, China.
⁴ School of Medicine, South China University of Technology, Guangzhou, 510655, China.

PMID: 38302073
DOI: 10.1093/ptj/pzae011

Abstract

Objective: Hypoxic-ischemic brain injury in infants often leads to hemiplegic motor dysfunction. The mechanism of their motor dysfunction has been attributed to deficiencies of the transcription factor SRY (sex-determining region) box 2 (Sox2) or the non-receptor-type tyrosine kinase Fyn (involved in neuronal signal transduction), which causes a defect in myelin formation. Constraint-induced movement therapy (CIMT) following cerebral hypoxia-ischemia may stimulate myelin growth by regulating Sox2/Fyn, Ras homolog protein family A (RhoA), and Rho-associated kinase 2 (ROCK2) expression levels. This study investigated how Sox2/Fyn regulates myelin remodeling following CIMT to improve motor function in rats with hemiplegic cerebral palsy (HCP).

Methods: To investigate the mechanism of Sox2 involvement in myelin growth and neural function in rats with HCP, Lentivirus-Sox2 adeno-associated virus and negative control-Lenti-Sox2 adeno-associated virus were injected into the lateral ventricle. The rats were divided into a control group and an HCP group with different interventions (CIMT, Lenti-Sox2 [LS], or negative control-Lenti-Sox2 [NS] treatment), yielding the HCP, HCP plus CIMT (HCP + CIMT), HCP + LS, HCP + LS + CIMT, HCP + NS, and HCP + NS + CIMT groups. Front-limb suspension and RotaRod tests, Golgi-Cox staining, transmission electron microscopy, immunofluorescence staining, Western blotting, and quantitative polymerase chain reaction experiments were used to analyze motor function, dendrite/axon area, myelin ultrastructure, and the levels of expression of oligodendrocytes and Sox2/Fyn/RhoA/ROCK2 in the motor cortex.

Results: The rats in the HCP + LS + CIMT group had better values for motor function, dendrite/axon area, myelin ultrastructure, oligodendrocytes, and Sox2/Fyn/RhoA/ROCK2 expression in the motor cortex than rats in the HCP and HCP + NS groups. The improvement of motor function and myelin remodeling, the expression of oligodendrocytes, and the expression of Sox2/Fyn/RhoA/ROCK2 in the HCP + LS group were similar to those in the HCP + CIMT group.

Conclusion: CIMT might overcome RhoA/ROCK2 signaling by upregulating the transcription of Sox2 to Fyn in the brain to induce maturation and differentiation of oligodendrocytes, thereby promoting myelin remodeling and improving motor function in rats with HCP.Impact. The pathway mediated by Sox2/Fyn could be a promising therapeutic target for HCP.

Keywords: Cerebral Palsy; Constraint-Induced Movement Therapy; Fyn; Motor Dysfunction; Myelin Remodeling; Sox2.