Comparison of the Effects of Constraint-Induced Movement Therapy and Unconstraint Exercise on Oxidative Stress and Limb Function—A Study on Human Patients and Rats with Cerebral Infarction

Abstract

Most conventional post-stroke rehabilitation treatments do not involve imposed constraints of the unaffected limb. In contrast, Constraint-Induced Movement Therapy (CIMT) is comprised of massed task practice with the affected limb and constraint of the unaffected limb. CIMT is a promising rehabilitation technique used for motor recovery of affected limbs after stroke, but its effectiveness and mechanism are not fully understood. We compared the effects of the two exercise modes on limb function post-stroke in animal models and human subjects, and investigated whether oxidative stress response was involved in regulating the effects. We first conducted a randomized controlled trial (RCT), in which 84 subjects with cerebral infarction were assigned to dose-matched constraint-induced movement therapy (CIMT), or unconstraint exercise (UE), or conventional rehabilitation treatment. Motor functions of the limb are primary outcomes of the RCT measured using Brief Fugl–Meyer upper extremity score (FMA-UE), Ashworth score, and Barthel scale. Psychological influence of CIMT and UE was also examined using Self-Rating Depression Scale (SDS). Next, we investigated the effects of CIMT and UE in rats undergoing middle cerebral artery occlusion and reperfusion (MCAO/R). Motor function, infarct volume, and pathohistological changes were investigated by mNSS, MRI, and histological studies. The role of Keap1-Nrf2-ARE was investigated using qRT-PCR, Western blot, immunochemistry, immunofluorescence, and ELISA experiments. In RCT, patients taking CIMT had a higher score in FMA-UE, Barthel index, and SDS, and a lower score in modified Ashworth, compared to those taking UE. In rats receiving CIMT, motor function was increased, and infarct volume was decreased compared to those receiving UE. The expression of Keap1 protein and mRNA in the peri-infarct tissue was decreased, and Nrf2 and ARE protein and mRNA were increased in rats receiving CIMT compared with UE. Nrf2 agonist t-BHQ increased the benefits of CIMT. In conclusion, CIMT is more effective than UE in improving upper limb motor function, reducing muscle spasm in patients with cerebral infarction compared to UE, but patients receiving CIMT may feel depressed. Moreover, both CIMT and UE are beneficial to limb function recovery and limit the infarct expansion in MCAO/R rats, but CIMT was more effective than UE. Oxidative stress reaction has an essential role in regulating the CIMT induced benefits.