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Knockdown of MicroRNA-21 Promotes Neurological Recovery After Acute Spinal Cord Injury

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Abstract

To assess the therapeutic effects of microRNA-21 (miR-21) knockdown (KD) for acute thoracic spinal cord contusion using a mouse model. Forty C57/BL6 mice were randomly divided into four groups: mice in the sham-operated (Sham) group received surgical procedure without spinal cord contusion; the spinal cord injury (SCI) group mice underwent spinal cord contusion without treatment; mice in the miR-21 KD group underwent spinal cord contusion followed by a single dose subdural injection of miR-21 KD vectors (1 × 107 TU); and the negative control (NC) group mice were given subdural injection of comparable amount of NC vectors (1 × 107 TU) after spinal cord contusion. The Basso Mouse Scale (BMS) was employed to assess hindlimb motor functions. Hematoxylin–eosin and Luxol fast blue staining were performed to evaluate pathologic changes in spinal cord tissues. Peripheral blood serum levels of tumor necrosis factor α (TNFα), transforming growth factor β (TGF-β) and interleukin-1β (IL-1β) were determined by the enzyme-linked immunosorbent assay, and mRNA expression of Brain derived neurotrophic factor (BDNF) was examined by reverse transcription-polymerase chain reaction (RT-PCR). Western blotting was performed to analyze the AKT signaling pathway. KD of miRNA-21 effectively improved the BMS scores at day 14 post-surgery compared with the SCI group (p < 0.01). The spinal cord tissue in the miR-21 KD group displayed the most overt histologic signs of recovery, with axonal regeneration and the recovery of neuronal morphology at day 14 post-surgery. Significantly alleviation of TGF-β1, TNF-α and IL-1β was also found in sera from the miR-21 inhibition group in comparison to others, whereas BDNF gene expression was upregulated following miR-21 KD (p < 0.01). Further, significantly decreased AKT phosphorylation activity was illustrated in the miR-21 KD group (p < 0.001). The data suggest that miR-21 KD significantly reduces the inflammatory response at the damaged spinal cord site and promotes motor functional recovery. The treatment also elevated expression of BDNF, a neurotrophin participating in nerve regeneration.

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Acknowledgements

The authors wish to thank Dr. Guo-Dong Tang for his expertise and technical assistance. This work is supported by the National Natural Science Funds of China (Nos. 81401014, 81771346), the Chinese Postdoctoral Science Foundation (No. 2014M561935), the Natural Science Funds of Shandong Province (No. ZR2016HP41), the Chinese Postdoctoral Science Foundation (No. 2015T80725), and the Technology Research and Development Program of Jinan City (No. 201704133).

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Authors and Affiliations

  1. Department Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, 250013, Shandong, China

    Wei Xie, Ronghan Liu, Wenzhao Wang, Bin Ning & Tanghong Jia

  2. Department Emergency Medicine, Taishan Medical University, Taian, 271016, Shandong, China

    Wei Xie, Yadong Zhou & Jixue Shi

  3. Department Surgery - Orthopedics, University of Kansas School of Medicine-Wichita, Wichita, KS, 67214, USA

    Shang-you Yang

  4. Department Obstetrics and Gynecology, Affiliated Hospital of Taishan Medical University, Taian, 271000, Shandong, China

    Qianqian Zhang

  5. Department Ophthalmology, Affiliated Hospital of Taishan Medical University, Taian, 271000, Shandong, China

    Yi Wang

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  1. Wei Xie
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  2. Shang-you Yang
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  5. Yi Wang
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  7. Wenzhao Wang
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  9. Bin Ning
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  10. Tanghong Jia
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Correspondence to Bin Ning.

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Xie, W., Yang, Sy., Zhang, Q. et al. Knockdown of MicroRNA-21 Promotes Neurological Recovery After Acute Spinal Cord Injury. Neurochem Res 43, 1641–1649 (2018). https://doi.org/10.1007/s11064-018-2580-1

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  • DOI: https://doi.org/10.1007/s11064-018-2580-1

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