Open Access

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

  • Authors:
    • Hong Zhao
    • Zhen-Dong Liu
    • Yong-Bo Zhang
    • Xiao-Yu Gao
    • Cui Wang
    • Yi Liu
    • Xun-Fen Wang
  • View Affiliations

  • Published online on: October 11, 2021     https://doi.org/10.3892/mmr.2021.12484
  • Article Number: 844
  • Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.
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December-2021
Volume 24 Issue 6

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Spandidos Publications style
Zhao H, Liu Z, Zhang Y, Gao X, Wang C, Liu Y and Wang X: NEP1‑40 promotes myelin regeneration via upregulation of GAP‑43 and MAP‑2 expression after focal cerebral ischemia in rats. Mol Med Rep 24: 844, 2021
APA
Zhao, H., Liu, Z., Zhang, Y., Gao, X., Wang, C., Liu, Y., & Wang, X. (2021). NEP1‑40 promotes myelin regeneration via upregulation of GAP‑43 and MAP‑2 expression after focal cerebral ischemia in rats. Molecular Medicine Reports, 24, 844. https://doi.org/10.3892/mmr.2021.12484
MLA
Zhao, H., Liu, Z., Zhang, Y., Gao, X., Wang, C., Liu, Y., Wang, X."NEP1‑40 promotes myelin regeneration via upregulation of GAP‑43 and MAP‑2 expression after focal cerebral ischemia in rats". Molecular Medicine Reports 24.6 (2021): 844.
Chicago
Zhao, H., Liu, Z., Zhang, Y., Gao, X., Wang, C., Liu, Y., Wang, X."NEP1‑40 promotes myelin regeneration via upregulation of GAP‑43 and MAP‑2 expression after focal cerebral ischemia in rats". Molecular Medicine Reports 24, no. 6 (2021): 844. https://doi.org/10.3892/mmr.2021.12484