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Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion.

ABSTRACT: Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb. However, the molecular mechanism underlying its efficacy remains unclear. In this study, a middle cerebral artery occlusion (MCAO) rat model was produced by the suture method. Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days, starting from the 7th day after middle cerebral artery occlusion. Day 1 of treatment lasted for 10 minutes at 2 r/min, day 2 for 20 minutes at 2 r/min, and from day 3 onward for 20 minutes at 4 r/min. CatWalk gait analysis, adhesive removal test, and Y-maze test were used to investigate motor function, sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21st day after MCAO. On the 21st day after MCAO, the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay. The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography. The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats, but had no effect on cognitive function. The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3 (Gria3) in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1A, Avpr1a in the middle cerebral artery-occluded rats. In the ipsilateral hippocampus, only Adra2a was downregulated, and there was no significant change in Gria3. Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3, which is an ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor, within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region. The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged. Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion, but had no effect on Synapsin I levels. Besides, we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus. This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats, and suggests that these positive effects occur via the upregulation of the postsynaptic membrane ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 201802173S) on March 3, 2018.

SUBMITTER: Gao BY

PROVIDER: S-EPMC7034265 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion.

Gao Bei-Yao BY Xu Dong-Sheng DS Liu Pei-Le PL Li Ce C Du Liang L Hua Yan Y Hu Jian J Hou Jia-Yun JY Bai Yu-Long YL

Neural regeneration research 20200601 6

Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb. However, the molecular mechanism underlying its efficacy remains unclear. In this study, a middle cerebral artery occlusion (MCAO) rat model was produced by the suture method. Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days, starting fr ...[more]

PMID: 31823884

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Project description:Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A, RhoA, and Rho-associated kinase (ROCK) in the ischemic boundary zone. However, it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke. In addition, it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling. Here, a stroke model was established by middle cerebral artery occlusion and reperfusion. Seven days after stroke, the following treatments were initiated and continued for 3 weeks: forced limb use in constraint-induced movement therapy rats (constraint-induced movement therapy group), intraperitoneal infusion of fasudil (a ROCK inhibitor) in fasudil rats (fasudil group), or lateral ventricular injection of NEP1-40 (a specific antagonist of the Nogo-66 receptor) in NEP1-40 rats (NEP1-40 group). Immunohistochemistry and western blot assay results showed that, at 2 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone. However, at 4 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups, but there was no difference between these two groups. Compared with the ischemia/reperfusion group, modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion, especially in the constraint-induced movement therapy group. Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers (BrdU in combination with CD31 (platelet endothelial cell adhesion molecule), Nestin, doublecortin, NeuN, and glial fibrillary acidic protein) in the subventricular zone and ischemic boundary zone ipsilateral to the infarct. After 3 weeks of constraint-induced movement therapy, the number of regenerated nerve cells was noticeably increased, and was accompanied by an increased immune response of tight junctions (claudin-5), a pericyte marker (α-smooth muscle actin), and vascular endothelial growth factor receptor 2. Taken together, the results demonstrate that, compared with fasudil, constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion. In addition, constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40. Therefore, constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury, at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, China on December 9, 2015 (approval No. 2015PS326K).

Dataset Information

Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion.

Publications

Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion.

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