Constraint-Induced Movement Therapy Overcomes the Intrinsic Axonal Growth–Inhibitory Signals in Stroke Rats

Abstract

Forty-two male Wistar rats (200-250 g) were randomly assigned as sham-operated rats (SHAM; n=12), rats subjected to cerebral ischemia (ISC; n=15), and rats with cerebral ischemia that were later treated with CIMT (ISC+CIMT; n=15). All rats were housed under controlled temperature in a 12-hour light/dark cycle with easy access to food and water and assigned to groups with a minimum of 4 animals per enclosure. Protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University (permit No. SCXK [Liao] 2008-0005).Background and Purpose-Constraint-induced movement therapy (CIMT) improves functional outcome in patients with stroke possibly through structural plasticity. We hypothesized that CIMT could enhance axonal growth by overcoming the intrinsic growth-inhibitory signals, leading eventually to improved behavioral performance in stroke rats. Methods-Focal cerebral ischemia was induced by intracerebral injection of endothelin-1. Adult Wistar rats were divided into a sham-operated group, an ischemic group, and an ischemic group treated with CIMT. CIMT started at postoperative day 7 and continued for 3 weeks. Biotinylated dextran amine was injected into the contralateral sensorimotor cortex at postoperative day 14 to trace crossing axons at the cervical spinal cord. The expressions of Nogo-A, Nogo receptor, RhoA, and Rho-associated kinase in the peri-infarct cortex, and the expressions of biotinylated dextran amine, growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated spinal cord were measured by immunohistochemistry and Western blots. Behavioral recovery was analyzed at postoperative days 29 to 32. Results-Infarct volumes were not different between groups after stroke. CIMT significantly increased the length and the number of midline crossings of contralateral corticospinal axons to the denervated cervical spinal cord. CIMT significantly decreased the expressions of Nogo-A/Nogo receptor and RhoA/Rho-associated kinase in the peri-infarct cortex, and increased the expressions of growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated cervical spinal cord. Behavioral performances assessed by the beam-walking test and the water maze test were improved significantly by CIMT. Conclusions-CIMT promoted poststroke synaptic plasticity and axonal growth at least partially by overcoming the intrinsic growth-inhibitory signaling, leading to improved behavioral outcome. (Stroke. 2013;44:1698-1705.)

Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat

“…The reason for these contradictory results might lie in the different locations of the lesions (cortical vs subcortical). Use-dependent exaggeration of neuronal injury has been reported in cortical injury models [16,[25][26][27]. In addition, neuronal cell bodies seemed to be more vulnerable to excitotoxicity in contrast to their axons [10,12,28].…”

“…However, we must also consider the possibility that early CIMT can down-regulate inhibitory factors such as the Nogo-A receptor or RhoA/Rho-associated kinase [27]. neurons of the ipsi-lesional motor cortex, as has been reported in cases of denervated spinal cord [8].…”

Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke

“…Previous reports demonstrated that early application of forced impaired forelimb use facilitated the side switching of corticospinal fibers originating from the contralesional hemisphere in the cervical cord after transection of the unilateral pyramidal tract (Maier et al, 2008). These intraspinal recrossed sprouting fibers from the intact descending tract can also be an important substrate for recovery after unilateral motor cortex infarction (Zhao et al, 2013;Wahl et al, 2014). Conversely, the present data revealed that the ipsilesional affected motor cortex and its axons descending to the red nucleus were involved in FLU-induced reorganization and recovery after ICH, which perhaps depends on the extent of damage to the corticospinal system.…”

“…Brain imaging studies of stroke patients indicated that CIMT induced expansion of the forelimb representative area in the sensorimotor cortex after stroke (Liepert et al, 1998;Sawaki et al, 2008). Moreover, studies using rodent models reported forced impaired limb use-induced anatomical changes of the CNS such as sprouting from the ipsilateral corticospinal tract (CST) to the denervated cervical cord (Maier et al, 2008;Zhao et al, 2013). However, it has been difficult to demonstrate the causal linkage between reorganization of the circuit and behavioral recovery.…”

Sprouting of Brainstem–Spinal Tracts in Response to Unilateral Motor Cortex Stroke in Mice

“…When use of the left, stroke-affected paw was obligatory for a task (e.g., on the rotating rod) (Fig. 1C-E), performance gradually recovered, suggesting a functional recovery of the affected forepaw (Bury and Jones, 2002;Nakagawa et al, 2013;Zhao et al, 2013).…”