Skip to main content
Log in

Neuroprotective Effects of Melatonin on Experimental Allergic Encephalomyelitis Mice Via Anti-Oxidative Stress Activity

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a chronic auto-inflammatory disease of the central nervous system (CNS) and hard to heal. This study aimed to investigate the effect of melatonin on mice with experimental autoimmune encephalomyelitis (EAE), a widely used MS model, and its potential mechanism underlying the action of MT on anti-oxidative stress. Female C57BL/6 mice were injected with MOG35–55 peptide to set up the EAE model, and for detection of the effect of melatonin (10 mg/kg i.p.) on the development and progression of EAE. Combining immunohistochemistry, biochemical technology and western blot approaches, the potential molecular mechanism of melatonin on EAE was evaluated as the levels of oxidative stress and the expression of Nrf2/ARE signal pathway. Our experiments showed a change of oxidative stress and Nrf2/ARE pathway expression in different groups, demonstrating that oxidative stress is associated with the pathophysiology of EAE. The administration of melatonin exerts neuroprotective effects against EAE, notably in suppressing the progression of EAE and pathological changes (lymphocytic infiltration). Furthermore, the effect of melatonin was probably related to decrease of the levels of oxidative stress, by activation of the Nrf2/ARE pathway and increased levels of anti-oxidant enzymes HO-1 and NQO1 expression. So, melatonin may be a promising reagent for intervention for multiple sclerosis in the future, and even for other autoimmune diseases.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adamczyk-Sowa M, Pierzchala K, Sowa P, Mucha S, Sadowska-Bartosz I, Adamczyk J, Hartel M (2014a) Melatonin acts as antioxidant and improves sleep in MS patients. Neurochem Res 39:1585–1593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adamczyk-Sowa M, Pierzchala K, Sowa P, Polaniak R, Kukla M, Hartel M (2014b) Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol 65:543–550

    CAS  PubMed  Google Scholar 

  • Alvarez-Sanchez N, Cruz-Chamorro I, Lopez-Gonzalez A, Utrilla JC, Fernandez-Santos JM, Martinez-Lopez A, Lardone PJ, Guerrero JM, Carrillo-Vico A (2015a) Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance. Brain Behav Immun 50:101–114

    Article  CAS  PubMed  Google Scholar 

  • Alvarez-Sanchez N, Cruz-Chamorro I, Lopez-Gonzalez A, Utrilla JC, Fernandez-Santos JM, Martinez-Lopez A, Lardone PJ, Guerrero JM, Carrillo-Vico A (2015b) Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance. Brain Behav Immun 50:101–114

    Article  CAS  PubMed  Google Scholar 

  • Arora D, Bhatla SC (2017) Melatonin and nitric oxide regulate sunflower seedling growth under salt stress accompanying differential expression of cu/Zn SOD and Mn SOD. Free Radic Biol Med 106:315–328

    Article  CAS  PubMed  Google Scholar 

  • Bruck W, Stadelmann C (2005) The spectrum of multiple sclerosis: new lessons from pathology. Curr Opin Neurol 18:221–224

    Article  PubMed  Google Scholar 

  • Calvo JR, Gonzalez-Yanes C, Maldonado MD (2013) The role of melatonin in the cells of the innate immunity: a review. J Pineal Res 55:103–120

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27:189–200

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Vico A, Lardone PJ, Alvarez-Sanchez N, Rodriguez-Rodriguez A, Guerrero JM (2013) Melatonin: buffering the immune system. Int J Mol Sci 14:8638–8683

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen SJ, Huang SH, Chen JW, Wang KC, Yang YR, Liu PF, Lin GJ, Sytwu HK (2016a) Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis. Int Immunopharmacol 31:169–177

    Article  CAS  PubMed  Google Scholar 

  • Chen SJ, Huang SH, Chen JW, Wang KC, Yang YR, Liu PF, Lin GJ, Sytwu HK (2016b) Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis. Int Immunopharmacol 31:169–177

    Article  CAS  PubMed  Google Scholar 

  • Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, Ho PP, Lee LY, Sobel RA, Steinman L, Soares MP (2007) Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J Clin Invest 117:438–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517

    Article  CAS  PubMed  Google Scholar 

  • Croxford AL, Spath S, Becher B (2015) GM-CSF in Neuroinflammation: licensing myeloid cells for tissue damage. Trends Immunol 36:651–662

    Article  CAS  PubMed  Google Scholar 

  • Damasceno A, Moraes AS, Farias A, Damasceno BP, Dos SL, Cendes F (2015) Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: a preliminary study. J Neurol Sci 353:166–168

    Article  CAS  PubMed  Google Scholar 

  • Dimitrijevic M, Kotur-Stevuljevic J, Stojic-Vukanic Z, Vujnovic I, Pilipovic I, Nacka-Aleksic M, Leposavic G (2017) Sex difference in oxidative stress parameters in spinal cord of rats with experimental autoimmune encephalomyelitis: relation to neurological deficit. Neurochem Res 42:481–492

    Article  CAS  PubMed  Google Scholar 

  • Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489

    Article  CAS  PubMed  Google Scholar 

  • Ebers GC (2008) Environmental factors and multiple sclerosis. Lancet Neurol 7:268–277

    Article  PubMed  Google Scholar 

  • Farez MF, Mascanfroni ID, Mendez-Huergo SP, Yeste A, Murugaiyan G, Garo LP, Balbuena AM, Patel B, Ysrraelit MC, Zhu C, Kuchroo VK, Rabinovich GA, Quintana FJ, Correale J (2015) Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162:1338–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farhadi N, Oryan S, Nabiuni M (2014) Serum levels of melatonin and cytokines in multiple sclerosis. Biom J 37:90–92

    Google Scholar 

  • Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M (2014) Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol 34:832–846

    Article  PubMed  PubMed Central  Google Scholar 

  • Garg N, Smith TW (2015) An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav 5:e362

    Article  Google Scholar 

  • Haider L, Fischer MT, Frischer JM, Bauer J, Hoftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H (2011) Oxidative damage in multiple sclerosis lesions. Brain 134:1914–1924

    Article  PubMed  PubMed Central  Google Scholar 

  • Hammann KP, Hopf HC (1986) Monocytes constitute the only peripheral blood cell population showing an increased burst activity in multiple sclerosis patients. Int Arch Allergy Appl Immunol 81:230–234

    Article  CAS  PubMed  Google Scholar 

  • Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. J Pineal Res 55:325–356

    CAS  PubMed  Google Scholar 

  • Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Yagishita Y, Suzuki T, Uruno A, Nakamura M, Nakao K, Furusako S, Yamamoto M (2017) The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur J Pharmacol 802:76–84

    Article  CAS  PubMed  Google Scholar 

  • Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Mochizuki M, Ishii Y, Ishii T, Shibata T, Kawamoto Y, Kelly V, Sekizawa K, Uchida K, Yamamoto M (2004) Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol Cell Biol 24:36–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA (2010) The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol Sci 114:237–246

    Article  CAS  PubMed  Google Scholar 

  • Jung KH, Hong SW, Zheng HM, Lee HS, Lee H, Lee DH, Lee SY, Hong SS (2010) Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J Pineal Res 48:239–250

    Article  CAS  PubMed  Google Scholar 

  • Kang JC, Ahn M, Kim YS, Moon C, Lee Y, Wie MB, Lee YJ, Shin T (2001) Melatonin ameliorates autoimmune encephalomyelitis through suppression of intercellular adhesion molecule-1. J Vet Sci 2:85–89

    CAS  PubMed  Google Scholar 

  • Kashani IR, Rajabi Z, Akbari M, Hassanzadeh G, Mohseni A, Eramsadati MK, Rafiee K, Beyer C, Kipp M, Zendedel A (2014) Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp Brain Res 232:2835–2846

    Article  CAS  PubMed  Google Scholar 

  • Keleku-Lukwete N, Suzuki M, Otsuki A, Tsuchida K, Katayama S, Hayashi M, Naganuma E, Moriguchi T, Tanabe O, Engel JD, Imaizumi M, Yamamoto M (2015) Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc Natl Acad Sci U S A 112:12169–12174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch M, Ramsaransing GS, Arutjunyan AV, Stepanov M, Teelken A, Heersema DJ, De Keyser J (2006) Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis. J Neurol 253:483–487

    Article  CAS  PubMed  Google Scholar 

  • Kutzelnigg A, Lassmann H (2014) Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol 122:15–58

    Article  PubMed  Google Scholar 

  • Langemann H, Kabiersch A, Newcombe J (1992) Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur Neurol 32:248–252

    Article  CAS  PubMed  Google Scholar 

  • Li B, Cui W, Liu J, Li R, Liu Q, Xie XH, Ge XL, Zhang J, Song XJ, Wang Y, Guo L (2013a) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249

    Article  CAS  PubMed  Google Scholar 

  • Li B, Cui W, Liu J, Li R, Liu Q, Xie XH, Ge XL, Zhang J, Song XJ, Wang Y, Guo L (2013b) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249

    Article  CAS  PubMed  Google Scholar 

  • Liu N, Kan QC, Zhang XJ, Xv YM, Zhang S, Zhang GX, Zhu L (2014) Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis. Exp Mol Pathol 97:470–476

    Article  CAS  PubMed  Google Scholar 

  • Maestroni GJ (2001) The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs 10:467–476

    Article  CAS  PubMed  Google Scholar 

  • Melamud L, Golan D, Luboshitzky R, Lavi I, Miller A (2012) Melatonin dysregulation, sleep disturbances and fatigue in multiple sclerosis. J Neurol Sci 314:37–40

    Article  CAS  PubMed  Google Scholar 

  • Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–499

    Article  CAS  PubMed  Google Scholar 

  • Ohl K, Tenbrock K, Kipp M (2016) Oxidative stress in multiple sclerosis: central and peripheral mode of action. Exp Neurol 277:58–67

    Article  CAS  PubMed  Google Scholar 

  • Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (1993) Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14:151–168

    Article  CAS  PubMed  Google Scholar 

  • Saito R, Suzuki T, Hiramoto K, Asami S, Naganuma E, Suda H, Iso T, Yamamoto H, Morita M, Baird L, Furusawa Y, Negishi T, Ichinose M, Yamamoto M (2015) Characterizations of three major Cysteine sensors of Keap1 in stress response. Mol Cell Biol 36:271–284

    PubMed  Google Scholar 

  • van Horssen J, Schreibelt G, Bo L, Montagne L, Drukarch B, van Muiswinkel FL, de Vries HE (2006) NAD(P)H:quinone oxidoreductase 1 expression in multiple sclerosis lesions. Free Radic Biol Med 41:311–317

    Article  PubMed  Google Scholar 

  • van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, de Vries HE (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 45:1729–1737

    Article  PubMed  Google Scholar 

  • van Horssen J, Witte ME, Schreibelt G, de Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 1812:141–150

    Article  PubMed  Google Scholar 

  • van Meeteren ME, Hendriks JJ, Dijkstra CD, van Tol EA (2004) Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease. Biochem Pharmacol 67:967–975

    Article  PubMed  Google Scholar 

  • Vriend J, Reiter RJ (2016) Melatonin, bone regulation and the ubiquitin-proteasome connection: a review. Life Sci 145:152–160

    Article  CAS  PubMed  Google Scholar 

  • Wen J, Ariyannur PS, Ribeiro R, Tanaka M, Moffett JR, Kirmani BF, Namboodiri AM, Zhang Y (2016) Efficacy of N-Acetylserotonin and melatonin in the EAE model of multiple sclerosis. J NeuroImmune Pharmacol 11:763–773

    Article  PubMed  Google Scholar 

  • Yang Y, Duan W, Jin Z, Yi W, Yan J, Zhang S, Wang N, Liang Z, Li Y, Chen W, Yi D, Yu S (2013) JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. J Pineal Res 55:275–286

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, Xue X, Xu Y, Meng D, Li B, Zhang M, Bin Z, Jin Z, Yu S, Yang Y, Wang H (2017) Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1alpha-SIRT3 signaling. Sci Rep 7:41337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We appreciate it very much that Professor Jiying Zhou of Chongqing Medical University has provided useful information and suggestions for this paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zuoxiao Li.

Ethics declarations

Conflicts of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Long, T., Yang, Y., Peng, L. et al. Neuroprotective Effects of Melatonin on Experimental Allergic Encephalomyelitis Mice Via Anti-Oxidative Stress Activity. J Mol Neurosci 64, 233–241 (2018). https://doi.org/10.1007/s12031-017-1022-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-017-1022-x

Keyword

Navigation