Skip to main content
SpringerLink
Log in

MicroRNAs in contusion spinal cord injury: pathophysiology and clinical utility

  • Review article
  • Published:
Acta Neurologica Belgica Aims and scope Submit manuscript

Abstract

Spinal cord injury (SCI) in humans is a common central nervous system trauma. Pathophysiologically, SCI involves both primary and secondary damages. Therapeutically, targeting secondary damage including inflammation, neuropathic pain, apoptosis, demyelination, and glial reaction to promote functional benefits for SCI patients has long been considered a potential treatment strategy by neuroscientists and clinicians. As a type of small non-coding RNA, microRNAs (miRNAs) have been shown to play essential roles in the regulation of pathophysiologic processes of SCI and are considered to be an effective treatment method for SCI. Dysregulated expression of miRNAs is observed in SCI patients and animal models of SCI. Furthermore, miRNAs might also be used as biomarkers for diagnostic and prognostic purposes in SCI. Given contusion injury is the most clinically relevant type of SCI, this review mainly focuses on the role of miRNAs in the pathophysiology of contusion SCI and the putative utilization of miRNAs as diagnostic biomarkers and therapeutic targets for contusion SCI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Song JL, Zheng W, Chen W, Qian Y, Ouyang YM, Fan CY (2017) Lentivirus-mediated microRNA-124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of spinal cord injury in rats. Exp Mol Med 49(5):e332

    Article  CAS  Google Scholar 

  2. Hayta E, Elden H (2018) Acute spinal cord injury: a review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat 87:25–31

    Article  CAS  Google Scholar 

  3. Zhu H, Xie R, Liu X, Shou J, Gu W, Gu S et al (2017) MicroRNA-494 improves functional recovery and inhibits apoptosis by modulating PTEN/AKT/mTOR pathway in rats after spinal cord injury. Biomed Pharmacother 92:879–887

    Article  CAS  Google Scholar 

  4. Fu X, Shen Y, Wang W, Li X (2018) MiR-30a-5p ameliorates spinal cord injury-induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling. Clin Exp Pharmacol Physiol 45(1):68–74

    Article  CAS  Google Scholar 

  5. Alizadeh A, Karimi-Abdolrezaee S (2016) Microenvironmental regulation of oligodendrocyte replacement and remyelination in spinal cord injury. J Physiol 594(13):3539–3552

    Article  CAS  Google Scholar 

  6. Bhalala OG, Srikanth M, Kessler JA (2013) The emerging roles of microRNAs in CNS injuries. Nat Rev Neurol 9(6):328–339

    Article  CAS  Google Scholar 

  7. Krichevsky AM (2007) MicroRNA profiling: from dark matter to white matter, or identifying new players in neurobiology. Sci World J 7:155–166

    Article  Google Scholar 

  8. Nieto-Diaz M, Esteban FJ, Reigada D, Munoz-Galdeano T, Yunta M, Caballero-Lopez M et al (2014) MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front Cell Neurosci 8:53

    Article  Google Scholar 

  9. Liu NK, Wang XF, Lu QB, Xu XM (2009) Altered microRNA expression following traumatic spinal cord injury. Exp Neurol 219(2):424–429

    Article  CAS  Google Scholar 

  10. Bak M, Silahtaroglu A, Moller M, Christensen M, Rath MF, Skryabin B et al (2008) MicroRNA expression in the adult mouse central nervous system. RNA 14(3):432–444

    Article  CAS  Google Scholar 

  11. Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG (2005) Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21(6):1469–1477

    Article  Google Scholar 

  12. Zhao X, He X, Han X, Yu Y, Ye F, Chen Y et al (2010) MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65(5):612–626

    Article  CAS  Google Scholar 

  13. Wang H, Moyano AL, Ma Z, Deng Y, Lin Y, Zhao C et al (2017) miR-219 cooperates with miR-338 in myelination and promotes myelin repair in the CNS. Dev Cell 40(6):566–582.e5

    Article  CAS  Google Scholar 

  14. Ruan W, Ning G, Feng S, Gao S, Hao Y (2018) MicroRNA381/Hes1 is a potential therapeutic target for spinal cord injury. Int J Mol Med 42(2):1008–1017

    CAS  PubMed  Google Scholar 

  15. Martirosyan NL, Carotenuto A, Patel AA, Kalani MY, Yagmurlu K, Lemole GM Jr et al (2016) The role of microRNA markers in the diagnosis, treatment, and outcome prediction of spinal cord injury. Front Surg 3:56

    PubMed  PubMed Central  Google Scholar 

  16. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773

    Article  CAS  Google Scholar 

  17. Hu JZ, Huang JH, Zeng L, Wang G, Cao M, Lu HB (2013) Anti-apoptotic effect of microRNA-21 after contusion spinal cord injury in rats. J Neurotrauma 30(15):1349–1360

    Article  Google Scholar 

  18. Yunta M, Nieto-Diaz M, Esteban FJ, Caballero-Lopez M, Navarro-Ruiz R, Reigada D et al (2012) MicroRNA dysregulation in the spinal cord following traumatic injury. PLoS One 7(4):e34534

    Article  CAS  Google Scholar 

  19. Strickland ER, Hook MA, Balaraman S, Huie JR, Grau JW, Miranda RC (2011) MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair. Neuroscience 186:146–160

    Article  CAS  Google Scholar 

  20. Nakanishi K, Nakasa T, Tanaka N, Ishikawa M, Yamada K, Yamasaki K et al (2010) Responses of microRNAs 124a and 223 following spinal cord injury in mice. Spinal Cord 48(3):192–196

    Article  CAS  Google Scholar 

  21. Li H, Zhao D, Zhang M (2016) Temporal expression MicroRNA-21 in serum of patients with spinal cord injury. In: International conference on biomedical and biological engineering, pp 116–122

  22. Wei J, Wang J, Zhou Y, Yan S, Li K, Lin H (2016) MicroRNA-146a contributes to SCI recovery via regulating TRAF6 and IRAK1 expression. BioMed Res Int 2016:4013487

    PubMed  PubMed Central  Google Scholar 

  23. Ning B, Gao L, Liu RH, Liu Y, Zhang NS, Chen ZY (2014) microRNAs in spinal cord injury: potential roles and therapeutic implications. Int J Biol Sci 10(9):997–1006

    Article  Google Scholar 

  24. Dong J, Lu M, He X, Xu J, Qin J, Cheng Z et al (2014) Identifying the role of microRNAs in spinal cord injury. Neurol Sci 35(11):1663–1671

    Article  Google Scholar 

  25. Jee MK, Jung JS, Choi JI, Jang JA, Kang KS, Im YB et al (2012) MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury. Brain 135(Pt 4):1237–1252

    Article  Google Scholar 

  26. Dai J, Xu LJ, Han GD, Sun HL, Zhu GT, Jiang HT et al (2018) MiR-137 attenuates spinal cord injury by modulating NEUROD4 through reducing inflammation and oxidative stress. Eur Rev Med Pharmacol Sci 22(7):1884–1890

    CAS  PubMed  Google Scholar 

  27. Gao L, Dai C, Feng Z, Zhang L, Zhang Z (2018) MiR-137 inhibited inflammatory response and apoptosis after spinal cord injury via targeting of MK2. J Cell Biochem 119(4):3280–3292

    Article  CAS  Google Scholar 

  28. Gaudet AD, Fonken LK, Watkins LR, Nelson RJ, Popovich PG (2018) MicroRNAs: roles in regulating neuroinflammation. Neuroscientist 24(3):221–245

    Article  CAS  Google Scholar 

  29. Shi Z, Zhou H, Lu L, Li X, Fu Z, Liu J et al (2017) The roles of microRNAs in spinal cord injury. Int J Neurosci 127(12):1104–1115

    Article  CAS  Google Scholar 

  30. Bhalala OG, Pan L, Sahni V, McGuire TL, Gruner K, Tourtellotte WG et al (2012) microRNA-21 regulates astrocytic response following spinal cord injury. J Neurosci 32(50):17935–17947

    Article  CAS  Google Scholar 

  31. Wang W, Tang S, Li H, Liu R, Su Y, Shen L et al (2018) MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma. Exp Cell Res 370:24–30

    Article  CAS  Google Scholar 

  32. Sahni V, Mukhopadhyay A, Tysseling V, Hebert A, Birch D, McGuire TL et al (2010) BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury. J Neurosci 30(5):1839–1855

    Article  CAS  Google Scholar 

  33. Wang W, Liu R, Su Y, Li H, Xie W, Ning B (2018) MicroRNA-21-5p mediates TGF-beta-regulated fibrogenic activation of spinal fibroblasts and the formation of fibrotic scars after spinal cord injury. Int J Biol Sci 14(2):178–188

    Article  CAS  Google Scholar 

  34. Chih-Yen W, Shang-Hsun Y, Shun-Fen T (2015) MicroRNA-145 as one negative regulator of astrogliosis. Glia 63(2):194–205

    Article  Google Scholar 

  35. Hong P, Jiang M, Li H (2014) Functional requirement of dicer1 and miR-17-5p in reactive astrocyte proliferation after spinal cord injury in the mouse. Glia 62(12):2044–2060

    Article  Google Scholar 

  36. Luan Y, Chen M, Zhou L (2017) MiR-17 targets PTEN and facilitates glial scar formation after spinal cord injuries via the PI3K/Akt/mTOR pathway. Brain Res Bull 128:68–75

    Article  CAS  Google Scholar 

  37. Sayed D, He M, Hong C, Gao S, Rane S, Yang Z et al (2010) MicroRNA-21 is a downstream effector of AKT that mediates its antiapoptotic effects via suppression of Fas ligand. J Biol Chem 285(26):20281–20290

    Article  CAS  Google Scholar 

  38. Liu NK, Xu XM (2011) MicroRNA in central nervous system trauma and degenerative disorders. Physiol Genomics 43(10):571–580

    Article  CAS  Google Scholar 

  39. Chandran R, Mehta SL, Vemuganti R (2017) Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int 111:12–22

    Article  CAS  Google Scholar 

  40. Xu Y, An BY, Xi XB, Li ZW, Li FY (2016) MicroRNA-9 controls apoptosis of neurons by targeting monocyte chemotactic protein-induced protein 1 expression in rat acute spinal cord injury model. Brain Res Bull 121:233–240

    Article  CAS  Google Scholar 

  41. Liu D, Huang Y, Jia C, Li Y, Liang F, Fu Q (2015) Administration of antagomir-223 inhibits apoptosis, promotes angiogenesis and functional recovery in rats with spinal cord injury. Cell Mol Neurobiol 35(4):483–491

    Article  CAS  Google Scholar 

  42. Liu XJ, Zheng XP, Zhang R, Guo YL, Wang JH (2015) Combinatorial effects of miR-20a and miR-29b on neuronal apoptosis induced by spinal cord injury. Int J Clin Exp Pathol 8(4):3811–3818

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shen Q, Feng ZY, Lu WC (2016) MicroRNA-137 inhibits apoptosis of neuron cells in injured spinal cord by targeting calpain 2. Int J Clin Exp Med 9(8):15:796–803

    CAS  Google Scholar 

  44. Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC et al (2014) Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain 15(1):40–48

    Article  Google Scholar 

  45. Cragg JJ, Noonan VK, Noreau L, Borisoff JF, Kramer JK (2015) Neuropathic pain, depression, and cardiovascular disease: a national multicenter study. Neuroepidemiology 44(3):130–137

    Article  Google Scholar 

  46. Wang Y, Ye F, Huang C, Xue F, Li Y, Gao S et al (2018) Bioinformatic analysis of potential biomarkers for spinal cord injured patients with intractable neuropathic pain. Clin J Pain 34:825–830

    PubMed  PubMed Central  Google Scholar 

  47. Favereaux A, Thoumine O, Bouali-Benazzouz R, Roques V, Papon MA, Salam SA et al (2011) Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. Embo J 30(18):3830–3841

    Article  CAS  Google Scholar 

  48. Willemen HL, Huo XJ, Mao-Ying QL, Zijlstra J, Heijnen CJ, Kavelaars A (2012) MicroRNA-124 as a novel treatment for persistent hyperalgesia. J Neuroinflam 9:143

    Article  CAS  Google Scholar 

  49. Sakai A, Suzuki H (2014) Emerging roles of microRNAs in chronic pain. Neurochem Int 77:58–67

    Article  CAS  Google Scholar 

  50. Plemel JR, Keough MB, Duncan GJ, Sparling JS, Yong VW, Stys PK et al (2014) Remyelination after spinal cord injury: is it a target for repair? Prog Neurobiol 117:54–72

    Article  CAS  Google Scholar 

  51. Liu S, Ren C, Qu X, Wu X, Dong F, Chand YK et al (2017) miR-219 attenuates demyelination in cuprizone-induced demyelinated mice by regulating monocarboxylate transporter 1. Eur J Neurosci 45(2):249–259

    Article  Google Scholar 

  52. Ujigo S, Kamei N, Hadoush H, Fujioka Y, Miyaki S, Nakasa T et al (2014) Administration of microRNA-210 promotes spinal cord regeneration in mice. Spine 39(14):1099–1107 (Phila Pa 1976)

    Article  Google Scholar 

  53. Jin L, Wu Z, Xu W, Hu X, Zhang J, Xue Z et al (2014) Identifying gene expression profile of spinal cord injury in rat by bioinformatics strategy. Mol Biol Rep 41(5):3169–3177

    Article  CAS  Google Scholar 

  54. Dai J, Xu LJ, Han GD, Sun HL, Zhu GT, Jiang HT et al (2018) MicroRNA-125b promotes the regeneration and repair of spinal cord injury through regulation of JAK/STAT pathway. Eur Rev Med Pharmacol Sci 22(3):582–589

    CAS  PubMed  Google Scholar 

  55. Zhou HJ, Wang LQ, Xu QS, Fan ZX, Zhu Y, Jiang H et al (2016) Downregulation of miR-199b promotes the acute spinal cord injury through IKK \(\upbeta\)-NF-\(\upkappa \text{ B }\) signaling pathway activating microglial cells. Exp Cell Res 349(1):60–67

    Article  CAS  Google Scholar 

  56. Rodrigues LF, Moura-Neto V (2018) TCLS ES. Biomarkers in spinal cord injury: from prognosis to treatment. Mol Neurobiol 55(8):6436–6448

    Article  CAS  Google Scholar 

  57. Shao Y, Chen Y (2016) Roles of circular RNAs in neurologic disease. Front Mol Neurosci 9:25

    Article  Google Scholar 

  58. Wang K (2017) The ubiquitous existence of MicroRNA in body fluids. Clin Chem 63(3):784–785

    Article  CAS  Google Scholar 

  59. Hachisuka S, Kamei N, Ujigo S, Miyaki S, Yasunaga Y, Ochi M (2014) Circulating microRNAs as biomarkers for evaluating the severity of acute spinal cord injury. Spinal Cord 52:596–600

    Article  CAS  Google Scholar 

  60. Tigchelaar S, Streijger F, Sinha S, Flibotte S, Manouchehri N, So K et al (2017) Serum MicroRNAs reflect injury severity in a large animal model of thoracic spinal cord injury. Sci Rep 7(1):1376

    Article  Google Scholar 

  61. Yan H, Hong P, Jiang M, Li H (2012) MicroRNAs as potential therapeutics for treating spinal cord injury. Neural Regen Res 7(17):1352–1359

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lin CA, Duan KY, Wang XW, Zhang ZS (2018) MicroRNA-409 promotes recovery of spinal cord injury by regulating ZNF366. Eur Rev Med Pharmacol Sci 22(12):3649–3655

    PubMed  Google Scholar 

  63. Jee MK, Jung JS, Im YB, Jung SJ, Kang SK (2012) Silencing of miR20a is crucial for Ngn1-mediated neuroprotection in injured spinal cord. Hum Gene Ther 23(5):508–520

    Article  CAS  Google Scholar 

  64. Kleaveland B, Shi CY, Stefano J, Bartel DP (2018) A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174(2):350–62

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant number 81261120563).

Author information

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191, People’s Republic of China

    Fang Li & Mou-Wang Zhou

Authors
  1. Fang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mou-Wang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FL conceived the content and wrote the critical review. MZ provided the ideas and supervised the work. Both authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Mou-Wang Zhou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This review does not require ethical approval at our institution.

Informed consent

This review does not have information that could identify the subject. According to the rules of Acta Neurologica Belgian, informed consent is not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, F., Zhou, MW. MicroRNAs in contusion spinal cord injury: pathophysiology and clinical utility. Acta Neurol Belg 119, 21–27 (2019). https://doi.org/10.1007/s13760-019-01076-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13760-019-01076-9

Keywords

Search

Navigation