Volume 11, Issue 1 (Vol.11 No.1 Apr 2022)                   rbmb.net 2022, 11(1): 63-73 | Back to browse issues page


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Govindasamy N, Chok K C, Ng P Y, Koh R Y, Chye S M. Melatonin Induced Schwann Cell Proliferation and Dedifferentiation Through NF-ĸB, FAKDependent but Src-Independent Pathways. rbmb.net. 2022; 11 (1) :63-73
URL: http://rbmb.net/article-1-692-en.html
Division of Biomedical Science and Biotechnology, School of Health Science, International Medical University.
Abstract:   (1599 Views)
Background: Peripheral nerve injury (PNI) is a common condition that compromises motor and sensory functions. Peripheral nerves are known to have regenerative capability and the pineal hormone, melatonin, is known to aid nerve regeneration. However, the role of Schwann cells and the pathways involved remain unclear. Thus, the aim of this study is to identify the effects of melatonin on Schwann cell proliferation, dedifferentiation, and the involvement of nuclear factor kappa light chain enhancer of activated B cells (NFĸB), focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase, Src pathways in this process.

Methods: Schwann cells was treated with melatonin and its proliferation and dedifferentiation were identified using MTT assay and immunofluorescence staining for SRY (sex determining region Y)-box 2 (SOX2). Next, the protein expressions of NF-ĸB, FAK and Src pathways were identified by Western blot.

Results: MTT results confirmed increased proliferation of Schwann cells with melatonin treatment, and it was highest at 10 μM melatonin. Immunofluorescent staining revealed an increase in the green fluorescence staining for SOX2 in melatonin-treated cells, showing enhanced dedifferentiation. Western blot assay revealed melatonin increased phospho-NF-ĸB (PNF-ĸB), IKK-α, FAK (D2R2E), phospho-FAK (Tyr 576/577 and Tyr 397) protein expressions as compared with control. However, Src (32G6), Lyn (C13F9), Fyn, Csk (C74C1) protein expressions were not increased as compared with control.

Conclusions: Melatonin promotes Schwann cell proliferation and dedifferentiation via NF-ĸB, FAKdependent but Src-independent pathways.
Full-Text [PDF 392 kb]   (465 Downloads)    
Type of Article: Original Article | Subject: Cell Biology
Received: 2021/04/25 | Accepted: 2021/08/15 | Published: 2022/05/26

References
1. Ciaramitaro P, Mondelli M, Logullo F, Grimaldi S, Battiston B, Sard A, et al. Traumatic peripheral nerve injuries: Epidemiological findings, neuropathic pain and quality of life in 158 patients. J Peripher Nerv Syst. 2010;15(2):120-7. [DOI:10.1111/j.1529-8027.2010.00260.x] [PMID]
2. Chen Z-L, Yu W-M, Strickland S. Peripheral Regeneration. Annu Rev Neurosci. 2007;30:209-33. [DOI:10.1146/annurev.neuro.30.051606.094337] [PMID]
3. Bhatheja K, Field J. Schwann cells: Origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol. 2006;38(12):1995-9. [DOI:10.1016/j.biocel.2006.05.007] [PMID]
4. Makwana M, Raivich G. Molecular mechanisms in successful peripheral regeneration. FEBS J. 2005;272(11):2628-38. [DOI:10.1111/j.1742-4658.2005.04699.x] [PMID]
5. Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ. Clinical Uses of Melatonin: Evaluation of Human Trials. Curr Med Chem. 2010;17(19):2070-95. [DOI:10.2174/092986710791233689] [PMID]
6. Shokouhi G, Tubbs RS, Shoja MM, Hadidchi S, Ghorbanihaghjo A, Roshangar L, et al. Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury. Childs Nerv Syst. 2008;24(1):111-7. [DOI:10.1007/s00381-007-0366-x] [PMID]
7. Daglioglu E, Dike MS, Kilinc K, Erdogan D, Take G, Ergungor F, et al. Neuroprotective Effect of Melatonin on Experimental Peripheral Nerve Injury : An Electron Microscopic and Biochemical Study. Cent Eur Neurosurg. 2009;70(3):109-14. [DOI:10.1055/s-0029-1220712] [PMID]
8. Yazar U, Cakir E, Boz C, Çobanoglu Ü, Baykal S. Electrophysiological , functional and histopathological assessments of high dose melatonin on regeneration after blunt sciatic nerve injury. J Clin Neuroscence. 2020;72:370-377. [DOI:10.1016/j.jocn.2020.01.006] [PMID]
9. Kaya Y, Sarikclglu L, Aslan M, Kencebey C, Demir N, Derin N, et al. Comparison of the beneficial effect of melatonin on recovery after cut and crush sciatic nerve injury : a combined study using functional , electrophysiological , biochemical , and electron microscopic analyses. Childs Nerv Syst. 2013;29(3):389-401. [DOI:10.1007/s00381-012-1936-0] [PMID]
10. Turgut M, Oktem G, Uysal A, Yurtseven ME. Immunohistochemical profile of transforming growth factor- b 1 and basic fibroblast growth factor in sciatic nerve anastomosis following pinealectomy and exogenous melatonin administration in rats. J Clin Neurosci. 2006;13(7):753-8. [DOI:10.1016/j.jocn.2005.07.019] [PMID]
11. Turgut M, Uysal A, Pehlivan M, Oktem G, Yurtseven ME. Assessment of effects of pinealectomy and exogenous melatonin administration on rat sciatic nerve suture repair : an electrophysiological , electron microscopic , and immunohistochemical study. Acta Neurochir (Wien). 2005;147(1):67-77. [DOI:10.1007/s00701-004-0426-x] [PMID]
12. Atik B, Erkutlu I, Tercan M, Buyukhatipoglu H, Bekerecioglu M, Pence S. The Effects of Exogenous Melatonin on Peripheral Nerve Regeneration and Collagen Formation in Rats. J Surg Res. 2011;166(2):330-6. [DOI:10.1016/j.jss.2009.06.002] [PMID]
13. Turgut M, Uyanikgil Y, Baka M, Tunç AT, Yavaşoǧlu A, Yurtseven ME, et al. Pinealectomy exaggerates and melatonin treatment suppresses neuroma formation of transected sciatic nerve in rats: Gross morphological, histological and stereological analysis. J Pineal Res. 2005;38(4):284-91. [DOI:10.1111/j.1600-079X.2004.00205.x] [PMID]
14. Chang HM, Liu CH, Hsu WM, Chen LY, Wang HP, Wu TH, et al. Proliferative effects of melatonin on Schwann cells: Implication for nerve regeneration following peripheral nerve injury. J Pineal Res. 2014;56(3):322-32. [DOI:10.1111/jpi.12125] [PMID]
15. Ghazi N, Aali N, Shahrokhi VR, Mohajertehran F, Saghravanian N. Relative Expression of SOX2 and OCT4 in Oral Squamous Cell Carcinoma and Oral Epithelial Dysplasia. Reports Biochem Mol Biol. 2020;9(2):171-179. [DOI:10.29252/rbmb.9.2.171] [PMID] [PMCID]
16. Balakrishnan A, Stykel MG, Touahri Y, Stratton JA, Biernaskie J, Schuurmans C. Temporal Analysis of Gene Expression in the Murine Schwann Cell Lineage and the Acutely Injured Postnatal Nerve. PLoS One. 2016;11(4):e0153256 . [DOI:10.1371/journal.pone.0153256] [PMID] [PMCID]
17. Chan HH, Leong YQ, Voon SM, Pan ML, Leong CO, Lim CL, et al. Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells. Reports Biochem Mol Biol. 2021;9(4):417-425. [DOI:10.52547/rbmb.9.4.417] [PMID] [PMCID]
18. Castelnovo LF, Bonalume V, Melfi S, Ballabio M, Colleoni D, Magnaghi V. Schwann cell development, maturation and regeneration: A focus on classic and emerging intracellular signaling pathways. Neural Regen Res. 2017;12(7):1013-1023. [DOI:10.4103/1673-5374.211172] [PMID] [PMCID]
19. Le N, Nagarajan R, Wang JYT, Araki T, Schmidt RE, Milbrandt J. Analysis of Congenital Hypomyelinating Egr2 Lo / Lo Nerves Identifies Sox2 as an Inhibitor of Schwann Cell Differentiation and Myelination. Proc Natl Acad Sci U S A. 2005;102(7):2596-601. [DOI:10.1073/pnas.0407836102] [PMID] [PMCID]
20. Roberts SL, Dun X, Doddrell RDS, Mindos T, Drake LK, Onaitis MW, et al. Sox2 expression in Schwann cells inhibits myelination in vivo and induces influx of macrophages to the nerve. Development. 2017;144(17):3114-3125. https://doi.org/10.1242/jcs.210351 [DOI:10.1242/dev.150656] [PMID] [PMCID]
21. Torres-mejía E, Trümbach D, Kleeberger C, Dornseifer U, Orschmann T, Bäcker T, et al. Sox2 controls Schwann cell self-organization through fibronectin fibrillogenesis. Sci Rep. 2020;10(1):1984 . [DOI:10.1038/s41598-019-56877-y] [PMID] [PMCID]
22. Parrinello S, Napoli I, Ribeiro S, Digby PW, Fedorova M, Parkinson DB, et al. EphB Signaling Directs Peripheral Nerve Regeneration through Sox2-Dependent Schwann Cell Sorting. Cell. 2010;143(1):145-55. [DOI:10.1016/j.cell.2010.08.039] [PMID] [PMCID]
23. Yoon C, Korade Z, Carter BD. Protein Kinase A-Induced Phosphorylation of the p65 Subunit of Nuclear Factor-κB Promotes Schwann Cell Differentiation into a Myelinating Phenotype. J Neurosci. 2008;28(14):3738-46. [DOI:10.1523/JNEUROSCI.4439-07.2008] [PMID] [PMCID]
24. Nickols JC, Valentine W, Kanwal S, Carter BD. Activation of the transcription factor NF-κB in Schwann cells is required for peripheral myelin formation. Nat Neurosci. 2003;6(2):161-7. [DOI:10.1038/nn995] [PMID]
25. Grove M, Brophy PJ. FAK Is Required for Schwann Cell Spreading on Immature Basal Lamina to Coordinate the Radial Sorting of Peripheral Axons with Myelination. J Neurosci. 2014;34(40):13422-34. [DOI:10.1523/JNEUROSCI.1764-14.2014] [PMID] [PMCID]
26. Grove M, Komiyama NH, Nave K, Grant SG, Sherman DL, Brophy PJ. FAK is required for axonal sorting by Schwann cells. J Cell Biol. 2007;176(3):277-282. [DOI:10.1083/jcb.200609021] [PMID] [PMCID]
27. Okada M. Regulation of the Src Family Kinases by Csk. Int J Biol Sci. 2012;8(10):1385-97. [DOI:10.7150/ijbs.5141] [PMID] [PMCID]
28. Melfi S, Montt Guevara MM, Bonalume V, Ruscica M, Colciago A, Simoncini T, et al. Src and phospho-FAK kinases are activated by allopregnanolone promoting Schwann cell motility, morphology and myelination. J Neurochem. 2017;141(2):165-178. [DOI:10.1111/jnc.13951] [PMID]
29. Zhao Y, Takagawa K, Oya T, Yang H, Gao Z-Y, Kawaguchi M, et al. Active Src Expression Is Induced After Rat Peripheral Nerve Injury. Glia. 2003;42(2):184-93. [DOI:10.1002/glia.10223] [PMID]
30. Beau JM Le, Tedeschi B, Walter G. Increased Expression of pp60 c-src Protein-Tyrosine Kinase During Peripheral Nerve Regeneration. J Neurosci Res. 1991;28(2):299-309. [DOI:10.1002/jnr.490280217] [PMID]
31. Hossain S, Fragoso G, Mushynski WE, Almazan G. Regulation of peripheral myelination by Src-like kinases. Exp Neurol. 2010;226(1):47-57. [DOI:10.1016/j.expneurol.2010.08.002] [PMID]

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