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Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury
Previous studies have reported that the Rho-associated coiled-coil containing protein kinase 2 (ROCKII) and glycogen synthase kinase-3β (GSK)-3β signaling pathways are involved in axonal regeneration. The present study investigated the effects of the combined application of Y27632 (a ROCKII inhibito...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355718/ https://www.ncbi.nlm.nih.gov/pubmed/27840930 http://dx.doi.org/10.3892/mmr.2016.5918 |
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author | Zhang, Ge Lei, Fei Zhou, Qingzhong Feng, Daxiong Bai, Yongheng |
author_facet | Zhang, Ge Lei, Fei Zhou, Qingzhong Feng, Daxiong Bai, Yongheng |
author_sort | Zhang, Ge |
collection | PubMed |
description | Previous studies have reported that the Rho-associated coiled-coil containing protein kinase 2 (ROCKII) and glycogen synthase kinase-3β (GSK)-3β signaling pathways are involved in axonal regeneration. The present study investigated the effects of the combined application of Y27632 (a ROCKII inhibitor) and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8; a GSK-3β inhibitor) on neurite outgrowth and functional recovery in rats with spinal cord injury (SCI). A total of 90 female Sprague-Dawley rats were randomly allocated into six groups, and the SCI rats received daily administration of 1.6 mg/kg Y27632 for 2 weeks and/or 1 mg/kg TDZD-8 for 3 weeks via a catheter. Cellular apoptosis in the injured spinal cords was measured at each time point using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression levels of growth-associated protein-43 (GAP-43) were determined by immunohistochemical staining. In addition, an anterograde tracer was used to analyze axonal regeneration, the Basso Beattie Bresnahan locomotor rating scale (BBB) was analyzed, and the somatosensory evoked potential (SEP) test was conducted. The results demonstrated that SCI upregulated the number of apoptotic cells, increased GAP-43 expression and enhanced the latent periods of SEP, as compared with in mice that underwent a sham operation. Furthermore, SCI decreased the BBB scores and the SEP amplitudes. These injuries in the spinal cord were reduced following treatment with Y27632, TDZD-8, or their combined application, as detected by decreased apoptosis, the induction of axonal regeneration, and the promotion of functional recovery of the lower limbs. Although the BBB scores, and SEP amplitudes and latent periods were not significantly different among the three drug treatment groups, the combined application of Y27632 and TDZD-8 resulted in stronger axonal regenerative potency and a greater protective effect on secondary SCI. These results indicated that the combined application of Y27632 and TDZD-8 may more effectively protect against secondary SCI by inhibiting cellular apoptosis, enhancing GAP-43 expression and promoting neurite outgrowth in SCI rats, compared with Y27632 or TDZD-8 alone. |
format | Online Article Text |
id | pubmed-5355718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-53557182017-03-31 Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury Zhang, Ge Lei, Fei Zhou, Qingzhong Feng, Daxiong Bai, Yongheng Mol Med Rep Articles Previous studies have reported that the Rho-associated coiled-coil containing protein kinase 2 (ROCKII) and glycogen synthase kinase-3β (GSK)-3β signaling pathways are involved in axonal regeneration. The present study investigated the effects of the combined application of Y27632 (a ROCKII inhibitor) and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8; a GSK-3β inhibitor) on neurite outgrowth and functional recovery in rats with spinal cord injury (SCI). A total of 90 female Sprague-Dawley rats were randomly allocated into six groups, and the SCI rats received daily administration of 1.6 mg/kg Y27632 for 2 weeks and/or 1 mg/kg TDZD-8 for 3 weeks via a catheter. Cellular apoptosis in the injured spinal cords was measured at each time point using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression levels of growth-associated protein-43 (GAP-43) were determined by immunohistochemical staining. In addition, an anterograde tracer was used to analyze axonal regeneration, the Basso Beattie Bresnahan locomotor rating scale (BBB) was analyzed, and the somatosensory evoked potential (SEP) test was conducted. The results demonstrated that SCI upregulated the number of apoptotic cells, increased GAP-43 expression and enhanced the latent periods of SEP, as compared with in mice that underwent a sham operation. Furthermore, SCI decreased the BBB scores and the SEP amplitudes. These injuries in the spinal cord were reduced following treatment with Y27632, TDZD-8, or their combined application, as detected by decreased apoptosis, the induction of axonal regeneration, and the promotion of functional recovery of the lower limbs. Although the BBB scores, and SEP amplitudes and latent periods were not significantly different among the three drug treatment groups, the combined application of Y27632 and TDZD-8 resulted in stronger axonal regenerative potency and a greater protective effect on secondary SCI. These results indicated that the combined application of Y27632 and TDZD-8 may more effectively protect against secondary SCI by inhibiting cellular apoptosis, enhancing GAP-43 expression and promoting neurite outgrowth in SCI rats, compared with Y27632 or TDZD-8 alone. D.A. Spandidos 2016-12 2016-11-01 /pmc/articles/PMC5355718/ /pubmed/27840930 http://dx.doi.org/10.3892/mmr.2016.5918 Text en Copyright: © Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Zhang, Ge Lei, Fei Zhou, Qingzhong Feng, Daxiong Bai, Yongheng Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title | Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title_full | Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title_fullStr | Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title_full_unstemmed | Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title_short | Combined application of Rho-ROCKII and GSK-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
title_sort | combined application of rho-rockii and gsk-3β inhibitors exerts an improved protective effect on axonal regeneration in rats with spinal cord injury |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355718/ https://www.ncbi.nlm.nih.gov/pubmed/27840930 http://dx.doi.org/10.3892/mmr.2016.5918 |
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