Constraint-Induced Movement Therapy Promotes Neural Remodeling and Functional Reorganization by Overcoming Nogo-A/NgR/RhoA/ROCK Signals in Hemiplegic Cerebral Palsy Mice

Abstract

Background. Little is known about the induction of functional and brain structural reorganization in hemiplegic cerebral palsy (HCP) by constraint-induced movement therapy (CIMT). Objective. We aimed to explore the specific molecular mechanism of functional and structural plasticity related to CIMT in HCP. Methods. The mice were divided into a control group and HCP groups with different interventions (unconstraint-induced movement therapy [UNCIMT], CIMT or siRNA-Nogo-A [SN] treatment): the HCP, HCP+UNCIMT, HCP+CIMT, HCP+SN, and HCP+SN+CIMT groups. Rotarod and front-limb suspension tests, immunohistochemistry, Golgi-Cox staining, transmission electron microscopy, and Western blot analyses were applied to measure motor function, neurons and neurofilament density, dendrites/axon areas, myelin integrity, and Nogo-A/NgR/RhoA/ROCK expression in the motor cortex. Results. The mice in the HCP+CIMT group had better motor function, greater neurons and neurofilament density, dendrites/axon areas, myelin integrity, and lower Nogo-A/NgR/RhoA/ROCK expression in the motor cortex than the HCP and HCP+UNCIMT groups ( P < .05). Moreover, the expression of Nogo-A/NgR/RhoA/ROCK, the improvement of neural remodeling and motor function of mice in the HCP+SN group were similar to those in the HCP+CIMT group ( P > .05). The neural remodeling and motor function of the HCP+SN+CIMT group were significantly greater than those in the HCP+SN and HCP+CIMT groups ( P < .05). Motor function were positively correlated with the density of neurons ( r = 0.450 and 0.309, respectively; P < .05) and neurofilament ( r = 0.717 and 0.567, respectively; P < .05). Conclusions. CIMT might promote the remodeling of neurons, neurofilament, dendrites/axon areas, and myelin in the motor cortex by partially inhibiting the Nogo-A/NgR/RhoA/ROCK pathway, thereby promoting the improvement of motor function in HCP mice.

Underlying causes of cerebral palsy: public health perspectives

“…CIMT promoted sprouting of the axons and post-stroke motor recovery by blockade of NOGO-A/RhoA/ROCK transduction cascade (Fig. 1) [28].…”

The Effect of Constraint-Induced Movement Therapy Combined With Repetitive Transcranial Magnetic Stimulation on Hand Function in Preschool Children With Unilateral Cerebral Palsy: A Randomized Controlled Preliminary Study

“…One of the most popular treatments among clinicians and researchers is constraint-induced movement therapy (CIMT), with an emphasis on constraining the unaffected extremity and coupling task-related practice with the affected upper extremity, and increasing evidence proved the effect of CIMT in children with UCP (Reedman et al, 2017 ; Hoare et al, 2019 ; Ilieva and Ilieva, 2020 ; Simon-Martinez et al, 2020 ). What is more, it was proved that CIMT might promote neural remodeling and thereby improve motor function (Liu et al, 2021 ). However, the findings on the effect of CIMT on improving bimanual coordination are controversial (Reid et al, 2015 ; Hoare et al, 2019 ).…”

Association of Nogo-A Gene Polymorphisms with Cerebral Palsy in Southern China: A Case-Control Study

“…Considering that the positive rate of SNPs in CP is 14–19% [ 16 ], there are more potential SNPs variants that need to be further discovered and studied. Our team's previous studies found that neurite outgrowth inhibitor-A (Nogo-A) plays a vital role in the nerve remodeling and functional recovery of CP mice [ 31 ], but so far, there is no research to explore the role of Nogo-A gene in the development of CP.…”