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Melatonin Inhibits Neural Cell Apoptosis and Promotes Locomotor Recovery via Activation of the Wnt/β-Catenin Signaling Pathway After Spinal Cord Injury

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Abstract

The spinal cord is highly sensitive to spinal cord injury (SCI) by external mechanical damage, resulting in irreversible neurological damage. Activation of the Wnt/β-catenin signaling pathway can effectively reduce apoptosis and protect against SCI. Melatonin, an indoleamine originally isolated from bovine pineal tissue, exerts neuroprotective effects after SCI through activation of the Wnt/β-catenin signaling pathway. In this study, we demonstrated that melatonin exhibited neuroprotective effects on neuronal apoptosis and supported functional recovery in a rat SCI model by activating the Wnt/β-catenin signaling pathway. We found that melatonin administration after SCI significantly upregulated the expression of low-density lipoprotein receptor related protein 6 phosphorylation (p-LRP-6), lymphoid enhancer factor-1 (LEF-1) and β-catenin protein in the spinal cord. Melatonin enhanced motor neuronal survival in the spinal cord ventral horn and improved the locomotor functions of rats after SCI. Melatonin administration after SCI also reduced the expression levels of Bax and cleaved caspase-3 in the spinal cord and the proportion of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cells, but increased the expression level of Bcl-2. These results suggest that melatonin attenuated SCI by activating the Wnt/β-catenin signaling pathway.

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Abbreviations

SCI:

Spinal cord injury

p-LRP-6:

Low-density lipoprotein receptor related protein 6 phosphorylation

LEF-1:

Lymphoid enhancer factor-1

CNS:

Central nervous system

MT:

Melatonin

Nrf2:

Nuclear factor erythroid 2-related factor 2

HIF:

Hypoxia-inducible factor

NF-κB:

Nuclear factor kappa B

SOD:

Superoxide dismutase

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

GSH:

Glutathione

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

siRNA:

Small interference RNA

BBB:

Basso, Beattie, and Bresnahan scores

TUNEL:

Transferase-mediated deoxyuridine triphosphate nick end labeling

ANOVA:

One-way analysis of variance

SEM:

Standard error of the mean

References

  1. Campagnolo DI, Bartlett JA, Keller SE (2000) Influence of neurological level on immune function following spinal cord injury: a review. J Spinal Cord Med 23:121–128

    Article  CAS  PubMed  Google Scholar 

  2. Zhu SP, Wang ZG, Zhao YZ, Wu J, Shi HX, Ye LB, Wu FZ, Cheng Y, Zhang HY, He S, Wei X, Fu XB, Li XK, Xu HZ, Xiao J (2016) Gelatin nanostructured lipid carriers incorporating nerve growth factor inhibit endoplasmic reticulum stress-induced apoptosis and improve recovery in spinal cord injury. Mol Neurobiol 53:4375–4386

    Article  CAS  PubMed  Google Scholar 

  3. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809

    Article  CAS  PubMed  Google Scholar 

  4. Marchetti B, Pluchino S (2013) Wnt your brain be inflamed? Yes, it Wnt! Trends Mol Med 19:144–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. David MD, Cantí C, Herreros J (2010) Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling. J Neurosci Res 88:3011–3023

    Article  CAS  PubMed  Google Scholar 

  6. Varela-Nallar L, Alfaro IE, Serrano FG, Parodi J, Inestrosa NC (2010) Wingless-type family member 5 A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci USA 107:21164–21169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31:2670–2684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Polakis P (2000) Wnt signaling and cancer. Genes Dev 14:111–112

    Google Scholar 

  9. Cisternas P, Henriquez JP, Brandan E, Inestrosa NC (2014) Wnt signaling in skeletal muscle dynamics: myogenesis, neuromuscular synapse and fibrosis. Mol Neurobiol 49:574–589

    Article  CAS  PubMed  Google Scholar 

  10. Varelanallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:91–103

    Google Scholar 

  11. Rosso SB, Inestrosa NC, Rosso SB (2012) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:151–160

    Google Scholar 

  12. Silvaalvarez C, Arrázola MS, Godoy JA, Ordenes D, Inestrosa NC (2012) Canonical Wnt signaling protects hippocampal neurons from Aβ oligomers: role of non-canonical Wnt-5a/Ca2+ in mitochondrial dynamics. Front Cell Neurosci 7:97

    Google Scholar 

  13. Inestrosa NC, Arenas E (2009) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86

    Article  PubMed  Google Scholar 

  14. Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y, Mei X (2016) Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury. J Neurochem 138:139–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vanecek J (1998) Cellular mechanisms of melatonin action. Physiol Rev 78:687–721

    CAS  PubMed  Google Scholar 

  16. Chen HY, Chen TY, Lee MY, Chen ST, Hsu YS, Kuo YL, Chang GL, Wu TS, Lee EJ (2006) Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice. J Pineal Res 41:175–182

    Article  PubMed  Google Scholar 

  17. Bains M, Hall ED (2012) Antioxidant therapies in traumatic brain and spinal cord injury. Biochimica Et Biophysica Acta 1822:675–684

    Article  CAS  PubMed  Google Scholar 

  18. Naseem M, Parvez S (2014) Role of melatonin in traumatic brain injury and spinal cord injury. Sci World J 2014:586270–586270

    Article  Google Scholar 

  19. Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 54:1–14

    Article  CAS  PubMed  Google Scholar 

  20. Erten SF, Kocak A, Ozdemir I, Aydemir S, Colak A, Reeder BS (2003) Protective effect of melatonin on experimental spinal cord ischemia. Spinal Cord 41:533–538

    Article  CAS  PubMed  Google Scholar 

  21. Park S, Lee SK, Park K, Lee Y, Hong Y, Lee S, Jeon JC, Kim JH, Lee SR, Chang KT, Hong Y (2012) Beneficial effects of endogenous and exogenous melatonin on neural reconstruction and functional recovery in an animal model of spinal cord injury. J Pineal Res 52:107–119

    Article  CAS  PubMed  Google Scholar 

  22. Gao Y, Bai C, Zheng D, Li C, Zhang W, Li M, Guan W, Ma Y (2016) Combination of melatonin and Wnt-4 promotes neural cell differentiation in bovine amniotic epithelial cells and recovery from spinal cord injury. J Pineal Res 32:147–152

    Google Scholar 

  23. Jeong JK, Lee JH, Moon JH, Lee YJ, Park SY (2014) Melatonin-mediated β-catenin activation protects neuron cells against prion protein-induced neurotoxicity. J Pineal Res 57:427–434

    Article  CAS  PubMed  Google Scholar 

  24. Yang L, Yao M, Lan Y, Mo W, Sun YL, Wang J, Wang YJ, Cui XJ (2015) Melatonin for spinal cord injury in animal models: a systematic review and network meta-analysis. J Neurotrauma 33:290–300

    Article  Google Scholar 

  25. Allen AR (1911) Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column: a preliminary report. J Am Med Assoc 57:878–880

    Article  Google Scholar 

  26. Zhou Z, Chen S, Zhao H, Wang C, Gao K, Guo Y, Shen Z, Wang Y, Wang H, Mei X (2016) Probucol inhibits neural cell apoptosis via inhibition of mTOR signaling pathway after spinal cord injury. Neuroscience 329:193–200

    Article  CAS  PubMed  Google Scholar 

  27. Maqueda A, Arenas E (2011) Differential expression of Wnts after spinal cord contusion injury in adult rats. PloS ONE, 6:e27000–e27000

    Article  PubMed  PubMed Central  Google Scholar 

  28. Macdonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lin CL, Wang JY, Huang YT, Kuo YH, Surendran K, Wang FS (2006) Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells. J Am Soc Nephrol 17:2812–2820

    Article  CAS  PubMed  Google Scholar 

  30. Reya T, Clevers H (2015) Wnt signalling in stem cells and cancer. Cell Dev Biol 434:843–850

    Google Scholar 

  31. Liu Y, Wang X, Lu CC, Sherman R, Steward O, Xu XM, Zou Y (2008) Repulsive Wnt signaling inhibits axon regeneration following central nervous system injury. J Neurosci 28:8376–8382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Onishi K, Hollis E, Zou Y (2014) Axon guidance and injury-lessons from Wnts and Wnt signaling. Curr Opin Neurobiol 27 C:232–240

    Article  Google Scholar 

  33. Suh HI, Min J, Choi KH, Kim SW, Kim KS, Jeon SR (2011) Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats. Acta Neurochir 153:1003–1010

    Article  PubMed  Google Scholar 

  34. Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ (2013) WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 123:2268–2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang Z, Wu Y, Zheng L, Zhang C, Yang J, Shi M, Feng D, Wu Z, Wang YZ (2013) Conditioned medium of Wnt/β-catenin signaling-activated olfactory ensheathing cells promotes synaptogenesis and neurite growth in vitro. Cell Mol Neurobiol 33:983–990

    Article  CAS  PubMed  Google Scholar 

  36. González-Fernández C, Fernández-Martos CM, Shields SD, Arenas E, Javier RF (2014) Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury. J Neurotrauma 31:565–581

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  38. Green DR, Reed JC (2001) Mitochondria and apoptosis. J Anhui Inst Educ 252:1–15

    Google Scholar 

  39. Cavallucci V, D’Amelio M (2011) Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases. Curr Pharm Des 17:215–229

    Article  CAS  PubMed  Google Scholar 

  40. Bethea JR, Dietrich WD (2002) Targeting the host inflammatory response in traumatic spinal cord injury. Curr Opin Neurol 15:355–360

    Article  PubMed  Google Scholar 

  41. Li HT, Zhao XZ, Zhang XR, Li G, Jia ZQ, Sun P, Wang JQ, Fan ZK, Lv G (2015) Exendin-4 enhances motor function recovery via promotion of autophagy and inhibition of neuronal Apoptosis after spinal cord injury in rats. Mol Neurobiol 53:4073–4082

    Article  PubMed  Google Scholar 

  42. Zhang J, Cui Z, Feng G, Bao G, Xu G, Sun Y, Wang L, Chen J, Jin H, Jian L (2015) RBM5 and p53 expression after rat spinal cord injury: Implications for neuronal apoptosis. Int J Biochem Cell Biol 60C:43–52

    Article  Google Scholar 

  43. Snigdha S, Smith ED, Prieto GA, Cotman CW (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14–24

    Article  CAS  PubMed  Google Scholar 

  44. JAdams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  CAS  PubMed  Google Scholar 

  45. Rudel T (1999) Caspase inhibitors in prevention of apoptosis. Herz 24:236–241

    Article  CAS  PubMed  Google Scholar 

  46. Bilir B, Kucuk O, Moreno CS (2013) Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells. J Transl Med 11:1–12

    Article  Google Scholar 

  47. Gutierrez-Cuesta J, Tajes M, Jiménez A, Coto-Montes A, Camins A, Pallas M (2008) Evaluation of potential pro-survival pathways regulated by melatonin in a murine senescence model. J Pineal Res 45:497–505

    Article  CAS  PubMed  Google Scholar 

  48. Ming M, Wang S, Wu W, Senyuk V, Le Beau MM, Nucifora G, Qian Z (2012) Activation of Wnt/β-catenin protein signaling induces mitochondria-mediated apoptosis in hematopoietic progenitor cells. J Biol Chem 287:22683–22690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu S, Yeh TH, Singh VP, Shiva S, Krauland L, Li H, Zhang P, Kharbanda K, Ritov V, Monga SPS (2012) β-Catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice. Hepatology 55:931–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wei L, Sun C, Lei M, Li G, Yi L, Luo F, Li Y, Ding L, Liu Z, Li S (2013) Activation of Wnt/β-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity. J Mol Neurosci 49:105–115

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant Nos. 81471854, 81671907 and 81601727). The authors thank the other researchers for their valuable technical assistance in this work.

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Authors and Affiliations

  1. Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University (Xibei Hospital), Xi’an, China

    Zhaoliang Shen, Haoyu Wang & Xiaoqian Dang

  2. Department of Orthopedics, Second Hospital of Jinzhou, Jinzhou, China

    Zhaoliang Shen

  3. Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China

    Zhaoliang Shen, Zipeng Zhou & Yue Guo

  4. Jinzhou Medical University, Jinzhou, China

    Shuang Gao

  5. Department of Orthopedics, Jining NO.1 People’s Hospital, Jining, China

    Kai Gao

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  1. Zhaoliang Shen
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Correspondence to Xiaoqian Dang.

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Shen, Z., Zhou, Z., Gao, S. et al. Melatonin Inhibits Neural Cell Apoptosis and Promotes Locomotor Recovery via Activation of the Wnt/β-Catenin Signaling Pathway After Spinal Cord Injury. Neurochem Res 42, 2336–2343 (2017). https://doi.org/10.1007/s11064-017-2251-7

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  • DOI: https://doi.org/10.1007/s11064-017-2251-7

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