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NKCC1 Inhibition Attenuates Chronic Cerebral Hypoperfusion-Induced White Matter Lesions by Enhancing Progenitor Cells of Oligodendrocyte Proliferation

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Abstract

Cerebral white matter is vulnerable to ischemic condition. However, no effective treatment to alleviate or restore the myelin damage caused by chronic cerebral hypoperfusion has been found. Na+-K+-Cl− cotransporter 1 (NKCC1), a Na+-K+-Cl− cotransporter widely expressed in the central nervous system (CNS), involves in regulation of cell swelling, EAA release, cell apoptosis, and proliferation. Nevertheless, the role of NKCC1 in chronic hypoperfusion-induced white matter lesions (WMLs) has not been explored. Here, mice subjected to bilateral common carotid artery stenosis (BCAS) were used as model of chronic cerebral hypoperfusion; density of progenitor cells of oligodendrocyte (OPCs), oligodendrocytes (OLs), astrocytes, and microglia was assessed by immunofluorescent staining and Western blot analysis; working memory was examined by eight-arm radial maze test; expression of MAPK signaling pathway was determined by Western blot analysis. After BCAS, white matter integrity disruption and working memory impairment were observed. NKCC1 inhibition by bumetanide administration enhanced OPC proliferation, attenuated chronic hypoperfusion-induced white matter damage, and promoted recovery of neurological function. However, NKCC1 inhibition caused no significant change in the densities of GFAP- and Iba-1-positive cells in the corpus callosum. Bumetanide administration significantly increased the expression of p-ERK and decreased the expression of p-JNK and p-p38 in comparison to vehicle-BCAS groups. In conclusion, NKCC1 inhibition might significantly ameliorate chronic cerebral hypoperfusion-induced WMLs and cognitive impairment by enhancing progenitor cells of oligodendrocyte proliferation, and this protective function of bumetanide might be mediated by modulation of the MAPK signaling pathway.

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Abbreviations

BCAS:

Bilateral common carotid artery stenosis

CNS:

Central nervous system

MAG:

Myelin-associated glycoprotein

NKCC1:

Na+-K+-Cl− cotransporter 1

OLs:

Oligodendrocytes

OPCs:

Progenitor cells of oligodendrocyte

WMLs:

White matter lesions

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Acknowledgments

This work is supported by grants from National Natural Science Foundation of China (81471200 to X. Luo and 91332108 to W. Wang).

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Authors and Affiliations

  1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ying Yu, Peicai Fu, Zhiyuan Yu, Minjie Xie, Wei Wang & Xiang Luo

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  1. Ying Yu
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  2. Peicai Fu
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  3. Zhiyuan Yu
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  4. Minjie Xie
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  5. Wei Wang
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  6. Xiang Luo
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Corresponding author

Correspondence to Xiang Luo.

Ethics declarations

All the experiments were performed in accordance with the guidelines approved by the National Institute of Health Guide for the Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee at Tongji Medical College.

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Yu, Y., Fu, P., Yu, Z. et al. NKCC1 Inhibition Attenuates Chronic Cerebral Hypoperfusion-Induced White Matter Lesions by Enhancing Progenitor Cells of Oligodendrocyte Proliferation. J Mol Neurosci 64, 449–458 (2018). https://doi.org/10.1007/s12031-018-1043-0

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