Cargando…

NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats

Axon regeneration after lesions to the central nervous system (CNS) is largely limited by the presence of growth inhibitory molecules expressed in myelin. Nogo-A is a principal inhibitor of neurite outgrowth, and blocking the activity of Nogo-A can induce axonal sprouting and functional recovery. Ho...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhao, Hong, Liu, Zhen-Dong, Zhang, Yong-Bo, Gao, Xiao-Yu, Wang, Cui, Liu, Yi, Wang, Xun-Fen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524407/
https://www.ncbi.nlm.nih.gov/pubmed/34643252
http://dx.doi.org/10.3892/mmr.2021.12484
_version_ 1784585506118434816
author Zhao, Hong
Liu, Zhen-Dong
Zhang, Yong-Bo
Gao, Xiao-Yu
Wang, Cui
Liu, Yi
Wang, Xun-Fen
author_facet Zhao, Hong
Liu, Zhen-Dong
Zhang, Yong-Bo
Gao, Xiao-Yu
Wang, Cui
Liu, Yi
Wang, Xun-Fen
author_sort Zhao, Hong
collection PubMed
description Axon regeneration after lesions to the central nervous system (CNS) is largely limited by the presence of growth inhibitory molecules expressed in myelin. Nogo-A is a principal inhibitor of neurite outgrowth, and blocking the activity of Nogo-A can induce axonal sprouting and functional recovery. However, there are limited data on the expression of Nogo-A after CNS lesions, and the mechanism underlying its influences on myelin growth remains unknown. The aim of the present study was to observe the time course of Nogo-A after cerebral ischemia/reperfusion in rats using immunohistochemistry and western blot techniques, and to test the effect of its inhibitor Nogo extracellular peptide 1–40 (NEP1-40) on neural plasticity proteins, growth-associated binding protein 43 (GAP-43) and microtubule associated protein 2 (MAP-2), as a possible mechanism underlying myelin suppression. A classic model of middle cerebral artery occlusion (MCAO) was established in Sprague-Dawley rats, which were divided into three groups: i) MCAO model group; ii) MCAO + saline group; and iii) MCAO + NEP1-40 group. Rats of each group were divided into five subgroups by time points as follows: days 1, 3, 7, 14 and 28. Animals that only received sham operation were used as controls. The Nogo-A immunoreactivity was located primarily in the cytoplasm of oligodendrocytes. The number of Nogo-A immunoreactive cells significantly increased from day 1 to day 3 after MCAO, nearly returning to the control level at day 7, increased again at day 14 and decreased at day 28. Myelin basic protein (MBP) immunoreactivity in the ipsilateral striatum gradually decreased from day 1 to day 28 after ischemia, indicating myelin loss appeared at early time points and continuously advanced during ischemia. Then, intracerebroventricular infusion of NEP1-40, which is a Nogo-66 receptor antagonist peptide, was administered at days 1, 3 and 14 after MCAO. It was observed that GAP-43 considerably increased from day 1 to day 7 and then decreased to a baseline level at day 28 compared with the control. MAP-2 expression across days 1–28 significantly decreased after MCAO. Administration of NEP1-40 attenuated the reduction of MBP, and upregulated GAP-43 and MAP-2 expression at the corresponding time points after MCAO compared with the MCAO + saline group. The present results indicated that NEP1-40 ameliorated myelin damage and promoted regeneration by upregulating the expression of GAP-43 and MAP-2 related to neuronal and axonal plasticity, which may aid with the identification of a novel molecular mechanism of restriction in CNS regeneration mediated by Nogo-A after ischemia in rats.
format Online
Article
Text
id pubmed-8524407
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher D.A. Spandidos
record_format MEDLINE/PubMed
spelling pubmed-85244072021-10-20 NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats Zhao, Hong Liu, Zhen-Dong Zhang, Yong-Bo Gao, Xiao-Yu Wang, Cui Liu, Yi Wang, Xun-Fen Mol Med Rep Articles Axon regeneration after lesions to the central nervous system (CNS) is largely limited by the presence of growth inhibitory molecules expressed in myelin. Nogo-A is a principal inhibitor of neurite outgrowth, and blocking the activity of Nogo-A can induce axonal sprouting and functional recovery. However, there are limited data on the expression of Nogo-A after CNS lesions, and the mechanism underlying its influences on myelin growth remains unknown. The aim of the present study was to observe the time course of Nogo-A after cerebral ischemia/reperfusion in rats using immunohistochemistry and western blot techniques, and to test the effect of its inhibitor Nogo extracellular peptide 1–40 (NEP1-40) on neural plasticity proteins, growth-associated binding protein 43 (GAP-43) and microtubule associated protein 2 (MAP-2), as a possible mechanism underlying myelin suppression. A classic model of middle cerebral artery occlusion (MCAO) was established in Sprague-Dawley rats, which were divided into three groups: i) MCAO model group; ii) MCAO + saline group; and iii) MCAO + NEP1-40 group. Rats of each group were divided into five subgroups by time points as follows: days 1, 3, 7, 14 and 28. Animals that only received sham operation were used as controls. The Nogo-A immunoreactivity was located primarily in the cytoplasm of oligodendrocytes. The number of Nogo-A immunoreactive cells significantly increased from day 1 to day 3 after MCAO, nearly returning to the control level at day 7, increased again at day 14 and decreased at day 28. Myelin basic protein (MBP) immunoreactivity in the ipsilateral striatum gradually decreased from day 1 to day 28 after ischemia, indicating myelin loss appeared at early time points and continuously advanced during ischemia. Then, intracerebroventricular infusion of NEP1-40, which is a Nogo-66 receptor antagonist peptide, was administered at days 1, 3 and 14 after MCAO. It was observed that GAP-43 considerably increased from day 1 to day 7 and then decreased to a baseline level at day 28 compared with the control. MAP-2 expression across days 1–28 significantly decreased after MCAO. Administration of NEP1-40 attenuated the reduction of MBP, and upregulated GAP-43 and MAP-2 expression at the corresponding time points after MCAO compared with the MCAO + saline group. The present results indicated that NEP1-40 ameliorated myelin damage and promoted regeneration by upregulating the expression of GAP-43 and MAP-2 related to neuronal and axonal plasticity, which may aid with the identification of a novel molecular mechanism of restriction in CNS regeneration mediated by Nogo-A after ischemia in rats. D.A. Spandidos 2021-12 2021-10-11 /pmc/articles/PMC8524407/ /pubmed/34643252 http://dx.doi.org/10.3892/mmr.2021.12484 Text en Copyright: © Zhao et al. https://creativecommons.org/licenses/by-nc-nd/4.0/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
Zhao, Hong
Liu, Zhen-Dong
Zhang, Yong-Bo
Gao, Xiao-Yu
Wang, Cui
Liu, Yi
Wang, Xun-Fen
NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title_full NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title_fullStr NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title_full_unstemmed NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title_short NEP1-40 promotes myelin regeneration via upregulation of GAP-43 and MAP-2 expression after focal cerebral ischemia in rats
title_sort nep1-40 promotes myelin regeneration via upregulation of gap-43 and map-2 expression after focal cerebral ischemia in rats
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524407/
https://www.ncbi.nlm.nih.gov/pubmed/34643252
http://dx.doi.org/10.3892/mmr.2021.12484
work_keys_str_mv AT zhaohong nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT liuzhendong nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT zhangyongbo nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT gaoxiaoyu nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT wangcui nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT liuyi nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats
AT wangxunfen nep140promotesmyelinregenerationviaupregulationofgap43andmap2expressionafterfocalcerebralischemiainrats