Skip to main content

Advertisement

SpringerLink
Log in

Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Melatonin and N-acetylserotonin (NAS) are tryptophan metabolites that have potent anti-oxidant, anti-inflammatory and neuroprotective properties in several animal models of neurological injury and disease including multiple sclerosis (MS). The therapeutic effect of NAS has not been reported previously in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. Using a MOG-peptide induced EAE mouse model we examined the effects of melatonin and NAS on clinical score, inflammatory markers, free radical generation, and sparing of axons, oligodendrocytes and myelin. We found that NAS and melatonin reduced clinical scores when administered prior to or after symptom onset. This effect was more pronounced when melatonin and NAS were administrated prior to symptom onset whereby the appearance of motor symptoms was significantly delayed. Activated microglia and CD4+ T-cells were increased in the white matter of untreated EAE mice, with a return to near control levels after melatonin or NAS treatment. The expression of the NADPH oxidase component p67phox and inducible nitric oxide synthase (iNOS) was increased in the EAE mice as compared with controls, and both drug treated groups had significant reductions in their expression. Melatonin and NAS treatment significantly reduced the loss of mature oligodendrocytes, demyelination and axonal injury. Both compounds also significantly attenuated iNOS induction and reactive oxygen species (ROS) generation in lipopolysaccharide-activated microglia in culture. Our results show for the first time the therapeutic effects of NAS and confirm previous reports on the effectiveness of melatonin in the EAE model of MS.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Alvarez-Diduk R, Galano A, Tan DX, Reiter RJ (2015) N-acetylserotonin and 6-hydroxymelatonin against oxidative stress: implications for the overall protection exerted by melatonin. J Phys Chem B 119:8535–8543

    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 (2015) Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance. Brain Behav Immun 50:101–114

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Rodriguez M (2015) Multiple sclerosis: the role of melatonin and N-acetylserotonin. Mult Scler Relat Disord 4:112–123

    Article  PubMed  Google Scholar 

  • Blask DE, Hill SM (1986) Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture. J Neural Transm Suppl 21:433–449

    CAS  PubMed  Google Scholar 

  • Bonnefont-Rousselot D, Collin F (2010) Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology 278:55–67

    Article  CAS  PubMed  Google Scholar 

  • Calabrese V, Scapagnini G, Ravagna A, Bella R, Foresti R, Bates TE, Giuffrida Stella AM, Pennisi G (2002) Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. J Neurosci Res 70:580–587

    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  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen SJ, Huang SH, Chen JW, Wang KC, Yang YR, Liu PF, Lin GJ, Sytwu HK (2016) 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 

  • Cuzzocrea S, Reiter RJ (2002) Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem 2:153–165

    Article  CAS  PubMed  Google Scholar 

  • Darlington LG, Forrest CM, Mackay GM, Smith RA, Smith AJ, Stoy N, Stone TW (2010) On the biological importance of the 3-hydroxyanthranilic acid: anthranilic acid ratio. Int J Tryptophan Res 3:51–59

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding K, Xu J, Wang H, Zhang L, Wu Y, Li T (2015) Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. Neurochem Int 91:46–54

    Article  CAS  PubMed  Google Scholar 

  • Esposito E, Cuzzocrea S (2010) Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 8:228–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farez MF, Mascanfroni ID, Mendez-Huergo SP, Yeste A, Murugaiyan G, Garo LP, Balbuena, Aguirre ME, 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. Biomed J 37:90–92

    Article  PubMed  Google Scholar 

  • Guerrero JM, Reiter RJ (2002) Melatonin-immune system relationships. Curr Top Med Chem 2:167–179

    Article  CAS  PubMed  Google Scholar 

  • Jang SW, Liu X, Pradoldej S, Tosini G, Chang Q, Iuvone PM, Ye K (2010) N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc Natl Acad Sci U S A 107:3876–3881

    Article  CAS  PubMed  PubMed Central  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 

  • Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, Nitsch R, Bechmann I (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J 19:1347–1349

    CAS  PubMed  Google Scholar 

  • Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA (2005) Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci U S A 102:9936–9941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Lin W, Tchantchou F, Lai R, Wen J, Zhang Y (2011a) Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes. Mol Cell Neurosci 48:62–71

    Article  CAS  PubMed  Google Scholar 

  • Li S, Vana AC, Ribeiro R, Zhang Y (2011b) Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis. Neuroscience 184:107–119

    Article  CAS  PubMed  Google Scholar 

  • Lin RF, Lin TS, Tilton RG, Cross AH (1993) Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study. J Exp Med 178:643–648

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Gonzalez A, Alvarez-Sanchez N, Lardone PJ, Cruz-Chamorro I, Martinez-Lopez A, Guerrero JM, Reiter RJ, Carrillo-Vico A (2015) Melatonin treatment improves primary progressive multiple sclerosis: a case report. J Pineal Res 58:173–177

    Article  CAS  PubMed  Google Scholar 

  • Lotufo CM, Lopes C, Dubocovich ML, Farsky SH, Markus RP (2001) Melatonin and N-acetylserotonin inhibit leukocyte rolling and adhesion to rat microcirculation. Eur J Pharmacol 430:351–357

    Article  CAS  PubMed  Google Scholar 

  • Maddur MS, Miossec P, Kaveri SV, Bayry J (2012) Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 181:8–18

    Article  CAS  PubMed  Google Scholar 

  • Mancuso R, Hernis A, Agostini S, Rovaris M, Caputo D, Fuchs D, Clerici M (2015) Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS One 10:e0130715

  • Milo R, Kahana E (2010) Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 9:A387–A394

    Article  CAS  PubMed  Google Scholar 

  • Miossec P (2009) IL-17 and Th17 cells in human inflammatory diseases. Microbes Infect 11:625–630

    Article  CAS  PubMed  Google Scholar 

  • Pick E (2014) Role of the rho GTPase Rac in the activation of the phagocyte NADPH oxidase: outsourcing a key task. Small GTPases 5:e27952

  • Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129–1146

    CAS  PubMed  Google Scholar 

  • Reiter RJ, Tan DX, Gitto E, Sainz RM, Mayo JC, Leon J, Manchester LC, Vijayalaxmi, Kilic E, Kilic U (2004) Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol 56:159–170

    CAS  PubMed  Google Scholar 

  • Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnocki Z (2007) Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochim Pol 54:1–9

    CAS  PubMed  Google Scholar 

  • Sakurai K, Zou JP, Tschetter JR, Ward JM, Shearer GM (2002) Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J Neuroimmunol 129:186–196

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ (2012) Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs 21:819–831

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R (2016) Kynurenines and glutamate: multiple links and therapeutic implications. Adv Pharmacol 76:13–37

    Article  CAS  PubMed  Google Scholar 

  • Stone TW, Forrest CM, Darlington LG (2012) Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J 279:1386–1397

    Article  CAS  PubMed  Google Scholar 

  • Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34:136–143

    Article  CAS  PubMed  Google Scholar 

  • Sundaram G, Brew BJ, Jones SP, Adams S, Lim CK, Guillemin GJ (2014) Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. J Neuroinflammation 11:204

  • Vana AC, Li S, Ribeiro R, Tchantchou F, Zhang Y (2011) Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter. Exp Neurol 231:45–55

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Zheng J, Jiang Z, Shi C, Li J, Du X, Wang H, Jiang J, Wang X (2013) Protective effect of N-acetylserotonin against acute hepatic ischemia-reperfusion injury in mice. Int J Mol Sci 14:17680–17693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Wang J, Jiang J, Stavrovskaya IG, Li M, Li W, Wu Q, Zhang X, Luo C, Zhou S, Sirianni AC, Sarkar S, Kristal BS, Friedlander RM, Wang X (2014) N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J Neurosci 34:2967–2978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Prasanth S. Ariyannur

    Present address: Molecular Diagnostics Div., Department of Medical Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, India

Authors and Affiliations

  1. Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA

    Jie Wen, Rachel Ribeiro, Mikiei Tanaka, John R. Moffett, Aryan M.A. Namboodiri & Yumin Zhang

  2. Epilepsy Center, Department of Neurology, Scott and White Hospital, Texas A&M University, Temple, TX, USA

    Batool F. Kirmani

Authors
  1. Jie Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prasanth S. Ariyannur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mikiei Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John R. Moffett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Batool F. Kirmani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aryan M.A. Namboodiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yumin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Aryan M.A. Namboodiri or Yumin Zhang.

Ethics declarations

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Grant Support

this work was supported by grants from the National Multiple Sclerosis Society (RG3741 to YZ), the Defense Medical Research and Development Program (0130–15–0003-00002 to YZ), the Uniformed Services University (R0701Z to YZ) and the NINDS at the NIH (NS084206 to AN).

Additional information

Jie Wen, Prasanth S. Ariyannur, Rachel Ribeiro are Equal Contribution

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, J., Ariyannur, P.S., Ribeiro, R. et al. Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis. J Neuroimmune Pharmacol 11, 763–773 (2016). https://doi.org/10.1007/s11481-016-9702-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-016-9702-9

Keywords

Search

Navigation