Decreased urinary level of melatonin as a marker of disease severity in patients with multiple sclerosis.
AbstractMelatonin has both pro-inflammatory and anti-inflammatory properties depending on the stage of inflammation. Despite its therapeutic effect in alleviation of some symptoms of multiple sclerosis; the precise role of melatonin in MS pathogenesis remains a topic of debate. The aim of this study was to measure the urine level of one of melatonin products which is an index of serum melatonin level, in MS patients in the acute phase of relapse and control patients. We also analyzed different clinical and cognitive indices in order to find any correlation with melatonin level. Twenty eight patients who were diagnosed as relapsing-remitting MS, according to the revised McDonald criteria, along with 10 age- and sex-matched control subjects were recruited in our study. Here we showed that urine 6-sulphatoxymelatonin levels (aMT6s; the major metabolite of melatonin) were significantly lower in MS patients compared to control group. Interestingly, urine aMT6s levels significantly correlated with MS Functional Composite score, but not Expanded Disability Severity Score. Based on above findings, there might be new hope in developing a quantitative and objective measure to assess the MS severity especially in neurodegenerative diseases. However, our results should be analyzed cautiously. We didn't evaluate simultaneous level of 25-OH Vitamin D. It has been recently reported that there is a negative correlation between melatonin and vitamin D levels. Further studies are needed to confirm this hypothesis.
1. Dhib-Jalbut S. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 2007; 68(22Suppl 3):S13-21.
2. Racke MK. The role of B cells in multiple sclerosis:rationale for B-cell-targeted therapies. Curr Opin Neurol 2008; 21(Suppl 1):S9-S18.
3. Richter HG, Torres-Farfan C, Garcia-Sesnich J, Abarzua- Catalan L, Henriquez MG, Alvarez-Felmer M, et al. Rhythmic expression of functional MT1 melatonin receptors in the rat adrenal gland. ndocrinology 2008;149(3):995-1003.
4. Maestroni GJ, Conti A. Immuno-derived opioids as mediators of the immuno-enhancing and anti-stress action of melatonin. Acta Neurol (Napoli) 1991; 13(4):356-60.
5. Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmun Rev 2007; 6(8):537-42.
6. Sandyk R. Diurnal variations in vision and relations to circadian melatonin secretion in multiple sclerosis. Int J Neurosci 1995; 83(1-2):1-6.
7. Constantinescu CS. Melanin, melanocyte-stimulating hormone, and the susceptibility to autoimmune demyelination: a rationale for light therapy in multiple sclerosis. Med Hypotheses 1995; 45(5):455-8.
8. Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, et al. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 2006; 13(5-6):357-74.
9. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in humans. Science 1980; 210(4475):1267-9.
10. Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004; 25(3-4):177-95.
11. Reiter RJ, Tan DX, Manchester LC, Tamura H.Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage. J Physiol Pharmacol 2007;58(Suppl 6):5-22.
12. Ayre EA, Pang SF. 2-[125I]iodomelatonin binding sites in the testis and ovary: putative melatonin receptors in the gonads. Biol Signals 1994; 3(2):71-84.
13. Brown GM, Pang CS, Pang SF. Binding sites for 2- [125I]iodomelatonin in the adrenal gland. Biol Signals 1994; 3(2):91-8.
14. Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem 2002; 2(2):167-79.
15. Wrona D. Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 2006; 172(1-2):38-58.
16. Garcia-Maurino S, Gonzalez-Haba MG, Calvo JR, Rafii- El-Idrissi M, Sanchez-Margalet V, Goberna R, et al. Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 1997; 159(2):574-81.
17. Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci 2013;14(4):8638-83.
18. Pioli C, Caroleo MC, Nistico G, Doria G. Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol 1993; 15(4):463-8.
19. Nelson RJ, Demas GE. Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res Bull 1997; 44(4):423-30.
20. Lissoni P, Rovelli F, Meregalli S, Fumagalli L, Musco F, Brivio F, et al. Melatonin as a new possible anti- inflammatory agent. J Biol Regul Homeost Agents 1997;11(4):157-9.
21. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27(2):189-200.
22. Maestroni GJ, Conti A. Anti-stress role of the melatonin- immuno-opioid network: evidence for a physiological mechanism involving T cell-derived, immunoreactive beta-endorphin and MET-enkephalin binding to thymic opioid receptors. Int J Neurosci 1991; 61(3-4):289-98.
23. Whitacre CC, Dowdell K, Griffin AC. Neuroendocrine influences on experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 1998; 840:705-16.
24. Marrie RA. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 2004; 3(12):709-18.
25. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005; 58(6):840-6.
26. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33(11):1444-52.
27. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98.
28. Ansari NN, Naghdi S, Hasson S, Valizadeh L, Jalaie S.Validation of a Mini-Mental State Examination (MMSE) for the Persian Population: A Pilot Study. Appl Neuropsychol 2010; 17(3):190-5.
29. Harirchian MH, Nasergivechi S, Maddah M, Meysamie A, Amini H, Shandiz EE, et al. modified fatigue impact scale in Iranian patients with multiple sclerosis. Iran J Neurol 2013; 12(1):32-4.
30. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 2000;55(7):934-9.
31. Constantinescu CS, Hilliard B, Ventura E, Rostami A.Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis. Pathobiology 1997; 65(4):190-4.
32. Kang JC, Ahn M, Kim YS, Moon C, Lee Y, Wie MB, et al. Melatonin ameliorates autoimmune encephalomyelitis through suppression of intercellular adhesion molecule-1. J Vet Sci 2001; 2(2):85-9.
33. Sandyk R. Influence of the pineal gland on the expression of experimental allergic encephalomyelitis: possible relationship to the aquisition of multiple sclerosis. Int J Neurosci 1997; 90(1-2):129-33.
34. Jankovic BD, Isakovic K, Petrovic S. Effect of pinealectomy on immune reactions in the rat. Immunology 1970; 18(1):1-6.
35. Carrillo-Vico A, Garcia-Perganeda A, Naji L, Calvo JR, Romero MP, Guerrero JM. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 2003;60(10):2272-8.
36. Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF.Evidence for a direct action of melatonin on the immune system. Biol Signals 1994; 3(2):107-17.
37. Rafii-El-Idrissi M, Calvo JR, Harmouch A, Garcia- Maurino S, Guerrero JM. Specific binding of melatonin by purified cell nuclei from spleen and thymus of the rat. J Neuroimmunol 1998; 86(2):190-7.
38. Dean G, McLoughlin H, Brady R, Adelstein AM, Tallett- Williams J. Multiple sclerosis among immigrants in Greater London. Br Med J 1976; 1(6014):861-4.
39. Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000; 123( Pt 5):968-74.
40. Benloucif S, Burgess HJ, Klerman EB, Lewy AJ, Middleton B, Murphy PJ, et al. Measuring melatonin in humans. J Clin Sleep Med 2008; 4(1):66-9.
41. Rudick RA, Cutter G, Baier M, Fisher E, Dougherty D, Weinstock-Guttman B, et al. Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology 2001; 56(10):1324-30.
42. Bergamaschi R, Romani A, Versino M, Poli R, Cosi V.Clinical aspects of fatigue in multiple sclerosis. Funct Neurol 1997; 12(5):247-51.
43. Krupp L. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler 2006; 12(4):367-8.
44. Krupp LB, Christodoulou C. Fatigue in multiple sclerosis.Curr Neurol Neurosci Rep 2001; 1(3):294-8.
45. Golan D, Staun-Ram E, Glass-Marmor L, Idit L, Orit R, Sara D, et al. The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis. Brain Behav Immun 2013; 32:180–5.