Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis

References

• Hayes CE, Donald Acheson E. A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses. 2008;71(1):85–90.
   PubMed Web of Science ®Google Scholar
• Weinshenker BG. Epidemiology of multiple sclerosis. Neurol Clin. 1996;14(2):291–308.
   PubMed Web of Science ®Google Scholar
• Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Phys. 2004;70(10):1935–1944.
   PubMed Web of Science ®Google Scholar
• John GR. Investigation of astrocyte–oligodendrocyte interactions in human cultures In: Methods in molecular biology. Clifton (NJ); 2012. p. 401–414 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22144322
   Google Scholar
• Mirshafiey A, Asghari B, Ghalamfarsa G, et al. The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J. 2014;14(1):13–25 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24516744
   Google Scholar
• Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci. 1993;20(1):17–29.
   PubMed Web of Science ®Google Scholar
• Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011;(17 Suppl 5):S139–S145.
   PubMedGoogle Scholar
• Goldberg L, Edwards NC, Fincher C, et al. Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis. JMCP. 2009;5(7):543–555.
   Google Scholar
• Wallin MT, Culpepper WJ, Nichols E, et al. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(3):269–285 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30679040
   PubMed Web of Science ®Google Scholar
• Salehpoor G, Rezaei S, Hosseininezhad M. Quality of life in multiple sclerosis (MS) and role of fatigue, depression, anxiety, and stress: a bicenter study from north of Iran. Iran J Nurs Midwifery Res. 2014;19(6):593–599.
   PubMedGoogle Scholar
• Göksel Karatepe A, Kaya T, Günaydn R, et al. Quality of life in patients with multiple sclerosis. Int J Rehabil Res. 2011;34(4):290–298.
   PubMed Web of Science ®Google Scholar
• Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci. 2002;205(1):51–58.
   PubMed Web of Science ®Google Scholar
• Hartung DM, Bourdette DN, Ahmed SM, et al. The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: too big to fail? Neurology. 2015;84(21):2185–2192 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25911108
   PubMed Web of Science ®Google Scholar
• García-Domínguez JM, Maurino J, Martínez-Ginés ML, et al. Economic burden of multiple sclerosis in a population with low physical disability. BMC Public Health. 2019;19(1):609 [cited 2019 Jul 6]. Available from: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-6907-x
   PubMedGoogle Scholar
• Tobore TO. On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis. Neurol Clin Neurosci. 2019 [cited 2019 Sep 20]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ncn3.12335
   Web of Science ®Google Scholar
• Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011;9(3):409–416.
   PubMed Web of Science ®Google Scholar
• Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008;255(S1):3–11.
   PubMedGoogle Scholar
• Barin L, Salmen A, Disanto G, et al. The disease burden of multiple sclerosis from the individual and population perspective: which symptoms matter most? Mult Scler Relat Disord. 2018;25:112–121 [cited 2019 Jul 6]. Available from: https://www.sciencedirect.com/science/article/pii/S2211034818302220
   PubMed Web of Science ®Google Scholar
• Fujinami RS, von Herrath MG, Christen U, et al. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19(1):80–94.
   PubMed Web of Science ®Google Scholar
• Ghadirian P, Dadgostar B, Azani R, et al. A case–control study of the association between socio-demographic, lifestyle and medical history factors and multiple sclerosis. Can J Public Health. 2001;92(4):281–285.
   PubMed Web of Science ®Google Scholar
• Degelman ML, Herman KM. Smoking and multiple sclerosis: a systematic review and meta-analysis using the Bradford Hill criteria for causation. Mult Scler Relat Disord. 2017;17:207–216.
   PubMed Web of Science ®Google Scholar
• Mesliniene S, Ramrattan L, Giddings S, et al. Role of vitamin D in the onset, progression, and severity of multiple sclerosis. Endocrinol Pract. 2013;19(1):129–136.
   PubMed Web of Science ®Google Scholar
• Sloka S, Silva C, Pryse-Phillips W, et al. A quantitative analysis of suspected environmental causes of MS. Can J Neurol Sci. 2011;38(1):98–105.
   PubMed Web of Science ®Google Scholar
• Gregory SG, Schmidt S, Seth P, et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007;39(9):1083–1091.
   PubMed Web of Science ®Google Scholar
• Lundmark F, Duvefelt K, Iacobaeus E, et al. Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat Genet. 2007;39(9):1108–1113.
   PubMed Web of Science ®Google Scholar
• Salou M, Nicol B, Garcia A, et al. Involvement of CD8+ T cells in multiple sclerosis. Front Immunol. 2015; 6:604.
   PubMed Web of Science ®Google Scholar
• Korn T. Pathophysiology of multiple sclerosis. J Neurol. 2008;255(S6):2–6.
   PubMedGoogle Scholar
• Fletcher JM, Lalor SJ, Sweeney CM, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162(1):1–11.
   PubMed Web of Science ®Google Scholar
• Korn T. Pathophysiology of multiple sclerosis. J Neurol. 2008;255(S6):2–6.
   PubMedGoogle Scholar
• Romme Christensen J, Börnsen L, Hesse D, et al. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis. J Neuroinflamm. 2012;9(1):719.
   Google Scholar
• Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta Mol Basis Dis. 2010;1802(1):66–79.
   PubMed Web of Science ®Google Scholar
• Yong VW, Zabad RK, Agrawal S, et al. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci. 2007;259(1–2):79–84 [cited 2019 Jul 8]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17382965
   PubMed Web of Science ®Google Scholar
• Gold SM, Sasidhar MV, Morales LB, et al. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). Lab Invest. 2009;89(10):1076–1083 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19668239
   PubMed Web of Science ®Google Scholar
• Correale J, Bassani MM, de los M. Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS. J Neuroimmunol. 2003;140(1–2):198–209 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12864990
   PubMed Web of Science ®Google Scholar
• Lee MA, Palace J, Stabler G, et al. Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. Brain. 1999;122(2):191–197 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10071048
   PubMedGoogle Scholar
• Lichtinghagen R, Seifert T, Kracke A, et al. Expression of matrix metalloproteinase-9 and its inhibitors in mononuclear blood cells of patients with multiple sclerosis. J Neuroimmunol. 1999;99(1):19–26 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10496173
   PubMed Web of Science ®Google Scholar
• Huitinga I, Erkut ZA, Beurden D, et al. The hypothalamo-pituitary-adrenal axis in multiple sclerosis. Ann NY Acad Sci. 2003;992(1):118–128.
   PubMedGoogle Scholar
• Al Gawwam G, Sharquie IK. Serum glutamate is a predictor for the diagnosis of multiple sclerosis. Sci World J. 2017;2017:1.
   Google Scholar
• Frigo M, Cogo MG, Fusco ML, Gardinetti M, Frigeni B. Glutamate and multiple sclerosis. Curr Med Chem. 2012;19(9):1295–1299.
   PubMed Web of Science ®Google Scholar
• Srinivasan R, Sailasuta N, Hurd R, et al. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. 2005;128(5):1016–1025.
   PubMedGoogle Scholar
• Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Nature. 1995;377(6545):150–151.
   PubMed Web of Science ®Google Scholar
• Sadovnick AD, Dircks A, Ebers GC. Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet. 1999;56(2):118–122.
   PubMed Web of Science ®Google Scholar
• Oksenberg J, Barcellos L, Hauser S. Genetic aspects of multiple sclerosis. Semin Neurol. 1999;19(03):281–288.
   PubMedGoogle Scholar
• Oksenberg JR, Baranzini SE, Sawcer S, et al. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet. 2008;9(7):516–526.
   PubMed Web of Science ®Google Scholar
• McElroy JP, Oksenberg JR. Multiple sclerosis genetics 2010. Neurol Clin. 2011;29(2):219–231.
   PubMed Web of Science ®Google Scholar
• Sloka JS, Phillips P-W, Stefanelli M, et al. Co-occurrence of autoimmune thyroid disease in a multiple sclerosis cohort. J Autoimmune Dis. 2005;2(1):9.
   PubMedGoogle Scholar
• Karni A, Abramsky O. Association of MS with thyroid disorders. Neurology. 1999;53(4):883–885 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10489063
   PubMed Web of Science ®Google Scholar
• Barone D, Khelemsky S, Hercules D, et al. Prevalence of thyroid disease in a multiple sclerosis clinic cohort (P6.170). Neurology. 2014;82(10 Suppl):P6.170 [cited 2019 Jul 7]. Available from: https://n.neurology.org/content/82/10_Supplement/P6.170
   Google Scholar
• Thompson CC, Potter GB. Thyroid hormone action in neural development. Cereb Cortex. 2000;10(10):939–945.
   PubMed Web of Science ®Google Scholar
• Michalski J-P, Kothary R. Oligodendrocytes in a nutshell. Front Cell Neurosci. 2015;9:340.
   PubMed Web of Science ®Google Scholar
• Marta CB, Adamo AM, Soto EF, et al. Sustained neonatal hyperthyroidism in the rat affects myelination in the central nervous system. J Neurosci Res. 1998;53(2):251–259.
   PubMed Web of Science ®Google Scholar
• Barres BA, Lazar MA, Raff MC. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development. 1994;120(5):1097–1108.
   PubMed Web of Science ®Google Scholar
• Johe KK, Hazel TG, Muller T, et al. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 1996;10(24):3129–3140.
   PubMed Web of Science ®Google Scholar
• Calza L, Fernandez M, Giuliani A, et al. Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis. Proc Natl Acad Sci USA. 2002;99(5):3258–3263 [cited 2019 Jul 14]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11867745
   PubMed Web of Science ®Google Scholar
• Fernandez M, Giuliani A, Pirondi S, et al. Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. Proc Natl Acad Sci USA. 2004;101(46):16363–16368.
   PubMed Web of Science ®Google Scholar
• Zhang M, Zhan XL, Ma ZY, et al. Thyroid hormone alleviates demyelination induced by cuprizone through its role in remyelination during the remission period. Exp Biol Med (Maywood). 2015;240(9):1183–1196.
   PubMed Web of Science ®Google Scholar
• Silvestroff L, Bartucci S, Pasquini J, et al. Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination. Exp Neurol. 2012;235(1):357–367.
   PubMed Web of Science ®Google Scholar
• Zhang M, Ma Z, Qin H, et al. Thyroid hormone potentially benefits multiple sclerosis via facilitating remyelination. Mol Neurobiol. 2016;53(7):4406–4416 [cited 2019 Jul 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26243185
   PubMed Web of Science ®Google Scholar
• Farsetti A, Mitsuhashi T, Desvergne B, et al. Molecular basis of thyroid hormone regulation of myelin basic protein gene expression in rodent brain. J Biol Chem. 1991;266(34):23226–23232.
   PubMed Web of Science ®Google Scholar
• Strait KA, Carlson DJ, Schwartz HL, et al. Transient stimulation of myelin basic protein gene expression in differentiating cultured oligodendrocytes: a model for 3,5,3′-triiodothyronine-induced brain development. Endocrinology. 1997;138(2):635–641.
   PubMed Web of Science ®Google Scholar
• Ibarrola N, Rodríguez-Peña A. Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development. Brain Res. 1997;752(1–2):285–293.
   PubMed Web of Science ®Google Scholar
• Pombo PMG, Barettino D, Ibarrola N, et al. Stimulation of the myelin basic protein gene expression by 9-cis-retinoic acid and thyroid hormone: activation in the context of its native promoter. Mol Brain Res. 1999;64(1):92–100.
   PubMedGoogle Scholar
• De Vito P, Incerpi S, Pedersen JZ, et al. Thyroid hormones as modulators of immune activities at the cellular level. Thyroid. 2011;21(8):879–890.
   PubMed Web of Science ®Google Scholar
• Vitales-Noyola M, Ramos-Levi AM, Martínez-Hernández R, et al. Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine. 2017;57(3):409–417.
   PubMed Web of Science ®Google Scholar
• Esfahanian F, Ghelich R, Rashidian H, et al. Increased levels of serum interleukin-17 in patients with Hashimoto’s thyroiditis. Indian J Endocrinol Metab. 2017;21(4):551–554.
   PubMedGoogle Scholar
• Payghani C, Khani F, Zadeh AR, et al. The effect of levothyroxine on serum levels of interleukin 10 and interferon-gamma in rat model of multiple sclerosis. Adv Biomed Res. 2017;6:118 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28989911
   PubMedGoogle Scholar
• Ozenci V, Kouwenhoven M, Huang YM, et al. Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand J Immunol. 1999;49(5):554–561 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10320650
   PubMed Web of Science ®Google Scholar
• Mendes-de-Aguiar CBN, Alchini R, Decker H, et al. Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity. J Neurosci Res. 2008;86(14):3117–3125.
   PubMed Web of Science ®Google Scholar
• Losi G, Garzon G, Puia G. Nongenomic regulation of glutamatergic neurotransmission in hippocampus by thyroid hormones. Neuroscience. 2008;151(1):155–163.
   PubMed Web of Science ®Google Scholar
• Minden SL, Orav J, Reich P. Depression in multiple sclerosis. Gen Hosp Psychiatry. 1987;9(6):426–434.
   PubMed Web of Science ®Google Scholar
• Kim EY, Kim SH, Rhee SJ, et al. Relationship between thyroid-stimulating hormone levels and risk of depression among the general population with normal free T4 levels. Psychoneuroendocrinology. 2015;58:114–119.
   PubMed Web of Science ®Google Scholar
• Cohen K, Flint N, Shalev S, et al. Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αβγ integrin in myeloma cells. Oncotarget. 2014;5(15):6312–6322 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25071016
   PubMedGoogle Scholar
• Simpson S, Blizzard L, Otahal P, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1132–1141.
   PubMed Web of Science ®Google Scholar
• Tao C, Simpson S, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(12):1343–1349.
   PubMed Web of Science ®Google Scholar
• Mansouri B, Asadollahi S, Heidari K, et al. Risk factors for increased multiple sclerosis susceptibility in the Iranian population. J Clin Neurosci. 2014;21(12):2207–2211.
   PubMed Web of Science ®Google Scholar
• Bäärnhielm M, Hedström AK, Kockum I, et al. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. Eur J Neurol. 2012;19(7):955–962.
   PubMed Web of Science ®Google Scholar
• Mirzaei F, Michels KB, Munger K, et al. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol. 2011;70(1):30–40.
   PubMed Web of Science ®Google Scholar
• Kampman MT, Wilsgaard T, Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J Neurol. 2007;254(4):471–477.
   PubMed Web of Science ®Google Scholar
• Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832.
   PubMed Web of Science ®Google Scholar
• Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60–65.
   PubMed Web of Science ®Google Scholar
• Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220–1224.
   PubMed Web of Science ®Google Scholar
• Brola W, Sobolewski P, Szczuchniak W, et al. Association of seasonal serum 25-hydroxyvitamin D levels with disability and relapses in relapsing-remitting multiple sclerosis. Eur J Clin Nutr. 2016;70(9):995–999.
   PubMed Web of Science ®Google Scholar
• Simpson S, Taylor B, Blizzard L, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in MS. Ann Neurol. 2010;68(2).
   PubMed Web of Science ®Google Scholar
• Shahbeigi S, Pakdaman H, Fereshtehnejad S-M, et al. Vitamin D3 concentration correlates with the severity of multiple sclerosis. Int J Prev Med. 2013;4(5):585–591.
   PubMedGoogle Scholar
• Harandi AA, Shahbeigi S, Pakdaman H, et al. Association of serum 25(OH) vitamin D3 concentration with severity of multiple sclerosis. Iran J Neurol. 2012;11(2):54–58.
   PubMedGoogle Scholar
• Thouvenot E, Orsini M, Daures J-P, et al. Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis. Eur J Neurol. 2015;22(3):564–569.
   PubMed Web of Science ®Google Scholar
• Oliveira SR, Simão ANC, Alfieri DF, et al. Vitamin D deficiency is associated with disability and disease progression in multiple sclerosis patients independently of oxidative and nitrosative stress. J Neurol Sci. 2017;381:213–219.
   PubMed Web of Science ®Google Scholar
• Wergeland S, Torkildsen Ø, Myhr K-M, et al. Dietary vitamin D3 supplements reduce demyelination in the cuprizone model. PLoS One. 2011;6(10):e26262.
   PubMed Web of Science ®Google Scholar
• Nystad AE, Wergeland S, Aksnes L, et al. Effect of high-dose 1.25 dihydroxyvitamin D3 on remyelination in the cuprizone model. APMIS. 2014;122(12):1178–1186.
   PubMed Web of Science ®Google Scholar
• de la Fuente AG, Errea O, van Wijngaarden P, et al. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol. 2015;211(5):975–985.
   PubMed Web of Science ®Google Scholar
• Adzemovic MZ, Zeitelhofer M, Hochmeister S, et al. Efficacy of vitamin D in treating multiple sclerosis-like neuroinflammation depends on developmental stage. Exp Neurol. 2013;249:39–48 [cited 2019 Jul 11]. Available from: https://www.sciencedirect.com/science/article/pii/S0014488613002422
   PubMed Web of Science ®Google Scholar
• Khoo A-L, Chai LYA, Koenen H, et al. Vitamin D3 down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. Cytokine. 2011;55(2):294–300.
   PubMed Web of Science ®Google Scholar
• Barrera D, Díaz L, Noyola-Martínez N, et al. Vitamin D and inflammatory cytokines in healthy and preeclamptic pregnancies. Nutrients. 2015;7(8):6465–6490.
   PubMed Web of Science ®Google Scholar
• Heine G, Niesner U, Chang H-D, et al. 1,25-dihydroxyvitamin D3 promotes IL-10 production in human B cells. Eur J Immunol. 2008;38(8):2210–2218.
   PubMed Web of Science ®Google Scholar
• Lysandropoulos AP, Jaquiéry E, Jilek S, et al. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J Neuroimmunol. 2011;233(1–2):240–244.
   PubMed Web of Science ®Google Scholar
• Hayes CE, Hubler SL, Moore JR, et al. Vitamin D actions on CD4(+) T cells in autoimmune disease. Front Immunol. 2015;6:100.
   PubMed Web of Science ®Google Scholar
• Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009;132(5):1146–1160.
   PubMed Web of Science ®Google Scholar
• Smolders J, Thewissen M, Peelen E, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 2009;4(8):e6635.
   PubMed Web of Science ®Google Scholar
• Nataf S, Garcion E, Darcy F, et al. 1,25 Dihydroxyvitamin D3 exerts regional effects in the central nervous system during experimental allergic encephalomyelitis. J Neuropathol Exp Neurol. 1996;55(8):904–914.
   PubMed Web of Science ®Google Scholar
• Joshi S, Pantalena L-C, Liu XK, et al. 1,25-Dihydroxyvitamin D3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011;31(17):3653–3669.
   PubMed Web of Science ®Google Scholar
• Nashold FE, Miller DJ, Hayes CE. 1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2000;103(2):171–179.
   PubMed Web of Science ®Google Scholar
• Pedersen LB, Nashold FE, Spach KM, et al. 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res. 2007;85(11):2480–2490.
   PubMed Web of Science ®Google Scholar
• Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem. 2010;285(50):38751–38755.
   PubMed Web of Science ®Google Scholar
• Arundine M, Tymianski M. Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium. 2003;34(4–5):325–337.
   PubMed Web of Science ®Google Scholar
• Fleet JC. The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol. 2017;453:36–45.
   PubMed Web of Science ®Google Scholar
• Rolf L, Damoiseaux J, Huitinga I, et al. Stress-axis regulation by vitamin D3 in multiple sclerosis. Front Neurol. 2018;9:263.
   PubMedGoogle Scholar
• Ashtari F, Ajalli M, Shaygannejad V, et al. The relation between vitamin D status with fatigue and depressive symptoms of multiple sclerosis. J Res Med Sci. 2013;18(3):193–197.
   PubMed Web of Science ®Google Scholar
• Bøe Lunde HM, Aae TF, Indrevåg W, et al. Poor sleep in patients with multiple sclerosis. PLoS One. 2012;7(11):e49996.
   PubMed Web of Science ®Google Scholar
• McCarty DE, Reddy A, Keigley Q, et al. Vitamin D, race, and excessive daytime sleepiness. J Clin Sleep Med. 2012;8(6):693–697.
   PubMed Web of Science ®Google Scholar
• Jung YS, Chae CH, Kim YO, et al. The relationship between serum vitamin D levels and sleep quality in fixed day indoor field workers in the electronics manufacturing industry in Korea. Ann Occup Environ Med. 2017;29(1):25.
   PubMedGoogle Scholar
• Darwish H, Haddad R, Osman S, et al. Effect of vitamin D replacement on cognition in multiple sclerosis patients. Sci Rep. 2017;7(1):45926.
   PubMedGoogle Scholar
• Kim SH, Baek MS, Yoon DS, et al. Vitamin D inhibits expression and activity of matrix metalloproteinase in human lung fibroblasts (HFL-1) cells. Tuberc Respir Dis. 2014;77(2):73–80 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25237378
   PubMedGoogle Scholar
• Wang L-F, Tai C-F, Chien C-Y, et al. Vitamin D decreases the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 in fibroblasts derived from Taiwanese patients with chronic rhinosinusitis with nasal polyposis. Kaohsiung J Med Sci. 2015;31(5):235–240 [cited 2019 Jul 6]. Available from: https://www.sciencedirect.com/science/article/pii/S1607551X1500039X
   PubMed Web of Science ®Google Scholar
• Halder SK, Osteen KG, Al-Hendy A. Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Hum Reprod. 2013;28(9):2407–2416 [cited 2019 Jul 6]. Available from: https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/det265
   PubMed Web of Science ®Google Scholar
• Velimirović M, Jevtić Dožudić G, Selaković V, et al. Effects of vitamin D3 on the NADPH oxidase and matrix metalloproteinase 9 in an animal model of global cerebral ischemia. Oxid Med Cell Longev. 2018;2018:1–14 [cited 2019 Jul 6]. Available from: https://www.hindawi.com/journals/omcl/2018/3273654/
   Google Scholar
• Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95(12):787–796 [cited 2019 Jul 6]. https://academic.oup.com/qjmed/article-lookup/doi/10.1093/qjmed/95.12.787
   PubMed Web of Science ®Google Scholar
• Su K, Bourdette D, Forte M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol. 2013;4:169.
   PubMed Web of Science ®Google Scholar
• Sadeghian M, Mastrolia V, Rezaei Haddad A, et al. Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis. Sci Rep. 2016;6(1):33249.
   PubMedGoogle Scholar
• Carvalho KS. Mitochondrial dysfunction in demyelinating diseases. Semin Pediatr Neurol. 2013;20(3):194–201.
   PubMed Web of Science ®Google Scholar
• Carvalho AN, Lim JL, Nijland PG, et al. Glutathione in multiple sclerosis: more than just an antioxidant? Mult Scler. 2014;20(11):1425–1431.
   PubMed Web of Science ®Google Scholar
• Witte ME, Mahad DJ, Lassmann H, et al. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med. 2014;20(3):179–187.
   PubMed Web of Science ®Google Scholar
• Dutta R, Mcdonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol. 2006;59(3):478–489.
   PubMed Web of Science ®Google Scholar
• Madsen PM, Pinto M, Patel S, et al. Mitochondrial DNA double-strand breaks in oligodendrocytes cause demyelination, axonal injury, and CNS inflammation. J Neurosci. 2017;37(42):10185–10199.
   PubMed Web of Science ®Google Scholar
• Blokhin A, Vyshkina T, Komoly S, et al. Variations in mitochondrial DNA copy numbers in MS brains. J Mol Neurosci. 2008;35(3):283–287.
   PubMed Web of Science ®Google Scholar
• Ban M, Elson J, Walton A, et al. Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility. PLoS One. 2008;3(8):e2891.
   PubMed Web of Science ®Google Scholar
• Yu X, Koczan D, Sulonen A-M, et al. mtDNA nt13708A variant increases the risk of multiple sclerosis. PLoS One. 2008;3(2):e1530.
   PubMed Web of Science ®Google Scholar
• Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002;192(1):1–15.
   PubMed Web of Science ®Google Scholar
• Offen D, Gilgun-Sherki Y, Melamed E. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004;251(3):261–268.
   PubMed Web of Science ®Google Scholar
• Haider L, Fischer MT, Frischer JM, et al. Oxidative damage in multiple sclerosis lesions. Brain. 2011;134(7):1914–1924.
   PubMedGoogle Scholar
• Gonsette RE. Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J Neurol Sci. 2008;274(1–2):48–53.
   PubMed Web of Science ®Google Scholar
• Fiorini A, Koudriavtseva T, Bucaj E, et al. Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis. PLoS One. 2013;8(6):e65184.
   PubMed Web of Science ®Google Scholar
• Ortiz GG, Pacheco-Moisés FP, Bitzer-Quintero OK, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:1.
   Google Scholar
• Ravera S, Bartolucci M, Cuccarolo P, et al. Oxidative stress in myelin sheath: the other face of the extramitochondrial oxidative phosphorylation ability. Free Radic Res. 2015;49(9):1156–1164.
   PubMed Web of Science ®Google Scholar
• Oliveira SR, Kallaur AP, Simão ANC, et al. Oxidative stress in multiple sclerosis patients in clinical remission: association with the expanded disability status scale. J Neurol Sci. 2012;321(1–2):49–53.
   PubMed Web of Science ®Google Scholar
• Smith KJ, Kapoor R, Felts PA. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 2006;9(1):69–92.
   Google Scholar
• French HM, Reid M, Mamontov P, et al. Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res. 2009;87(14):3076–3087.
   PubMed Web of Science ®Google Scholar
• Andrews HE, Nichols PP, Bates D, et al. Mitochondrial dysfunction plays a key role in progressive axonal loss in multiple sclerosis. Med Hypotheses. 2005;64(4):669–677.
   PubMed Web of Science ®Google Scholar
• Su KG, Banker G, Bourdette D, et al. Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr Neurol Neurosci Rep. 2009;9(5):411–417.
   PubMed Web of Science ®Google Scholar
• Campbell GR, Mahad DJ. Mitochondria as crucial players in demyelinated axons: lessons from neuropathology and experimental demyelination. Autoimmune Dis. 2011;2011:262847.
   PubMedGoogle Scholar
• Campbell GR, Mahad DJ. Mitochondrial changes associated with demyelination: consequences for axonal integrity. Mitochondrion. 2012;12(2):173–179.
   PubMed Web of Science ®Google Scholar
• Wang P, Xie K, Wang C, et al. Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol. 2014;72(3–4):249–254.
   PubMed Web of Science ®Google Scholar
• Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med. 2011;208(3):417–420.
   PubMed Web of Science ®Google Scholar
• Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–193 [cited 2019 Jul 11]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25772897
   PubMed Web of Science ®Google Scholar
• Peterson JW, Bö L, Mörk S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50(3):389–400 [cited 2019 Jul 11]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11558796
   PubMed Web of Science ®Google Scholar
• Correale J, Farez MF. The role of astrocytes in multiple sclerosis progression. Front Neurol. 2015;6:180 [cited 2019 Jul 8]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26347709
   PubMed Web of Science ®Google Scholar
• Brosnan CF, Raine CS. The astrocyte in multiple sclerosis revisited. Glia. 2013;61(4):453–465 [cited 2019 Jul 8]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23322421
   PubMed Web of Science ®Google Scholar
• Pearson C. A therapeutic link between astrogliosis and remyelination in a mouse model of multiple sclerosis. J Neurosci. 2018;38(1):29–31 [cited 2019 Jul 9]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29298907
   PubMed Web of Science ®Google Scholar
• Ignatenko O, Chilov D, Paetau I, et al. Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy. Nat Commun. 2018;9(1):70.
   PubMedGoogle Scholar
• Tarabal O, Caraballo-Miralles V, Cardona-Rossinyol A, et al. Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy. J Neuropathol Exp Neurol. 2014;73(6):519–535.
   PubMed Web of Science ®Google Scholar
• Furuta T, Mukai A, Ohishi A, et al. Oxidative stress-induced increase of intracellular zinc in astrocytes decreases their functional expression of P2X7 receptors and engulfing activity. Metallomics. 2017;9(12):1839–1851.
   PubMed Web of Science ®Google Scholar
• Ishii T, Takanashi Y, Sugita K, et al. Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain. Aging Cell. 2017;16(1):39–51.
   PubMed Web of Science ®Google Scholar
• Pongkittiphan V, Chavasiri W, Supabphol R. Antioxidant effect of berberine and its phenolic derivatives against human fibrosarcoma cells. Asian Pac J Cancer Prev. 2015;16(13):5371–5376.
   PubMedGoogle Scholar
• Li Z, Geng Y-N, Jiang J-D, et al. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evidence-Based Complement Altern Med. 2014;2014:1–12.
   Google Scholar
• Moghaddam HK, Baluchnejadmojarad T, Roghani M, et al. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol. 2014;49(2):820–826.
   PubMed Web of Science ®Google Scholar
• Baydas G, Reiter RJ, Yasar A, et al. Melatonin reduces glial reactivity in the hippocampus, cortex, and cerebellum of streptozotocin-induced diabetic rats. Free Radic Biol Med. 2003;35(7):797–804.
   PubMed Web of Science ®Google Scholar
• Hadgkiss EJ, Jelinek GA, Weiland TJ, et al. The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis. Nutr Neurosci. 2015;18(3):125–136 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24628020
   PubMed Web of Science ®Google Scholar
• Esquifino AI, Cano P, Jimenez-Ortega V, et al. Immune response after experimental allergic encephalomyelitis in rats subjected to calorie restriction. J Neuroinflammation. 2007;4(1):6 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17254325
   PubMedGoogle Scholar
• Piccio L, Stark JL, Cross AH. Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukoc Biol. 2008;84(4):940–948 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18678605
   PubMed Web of Science ®Google Scholar
• Kafami L, Raza M, Razavi A, et al. Intermittent feeding attenuates clinical course of experimental autoimmune encephalomyelitis in C57BL/6 mice. Avicenna J Med Biotechnol. 2010;2(1):47–52 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23407146
   PubMedGoogle Scholar
• Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 2016;15(10):2136–2146 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27239035
   PubMed Web of Science ®Google Scholar
• Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59–63 [cited 2019 Jun 25]Available from: http://www.ncbi.nlm.nih.gov/pubmed/8658196
   PubMed Web of Science ®Google Scholar
• Buchowski MS, Hongu N, Acra S, et al. Effect of modest caloric restriction on oxidative stress in women, a randomized trial. PLoS One. 2012;7(10):e47079 [cited 2019 Jul 7]. Available from: https://dx.plos.org/10.1371/journal.pone.0047079
   PubMed Web of Science ®Google Scholar
• Walsh ME, Shi Y, Van Remmen H. The effects of dietary restriction on oxidative stress in rodents. Free Radic Biol Med. 2014;66:88–99 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23743291
   PubMed Web of Science ®Google Scholar
• Stankovic M, Mladenovic D, Ninkovic M, et al. Effects of caloric restriction on oxidative stress parameters. GPB. 2013;32(02):277–283 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23682026
   Google Scholar
• Brenton JN, Banwell B, Bergqvist AGC, et al. Pilot study of a ketogenic diet in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e565 [cited 2019 Jul 6]. Available from: http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000000565
   PubMed Web of Science ®Google Scholar
• Storoni M, Plant GT. The therapeutic potential of the ketogenic diet in treating progressive multiple sclerosis. Mult Scler Int. 2015;2015:681289 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26839705
   PubMedGoogle Scholar
• Kim DY, Hao J, Liu R, et al. Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One. 2012;7(5):e35476 [cited 2019 Jul 6]. Available from: https://dx.plos.org/10.1371/journal.pone.0035476
   PubMed Web of Science ®Google Scholar
• Sedaghat F, Jessri M, Behrooz M, et al. Mediterranean diet adherence and risk of multiple sclerosis: a case–control study. Asia Pac J Clin Nutr. 2016;25(2):377–384.
   PubMed Web of Science ®Google Scholar
• Dai J, Jones DP, Goldberg J, et al. Association between adherence to the Mediterranean diet and oxidative stress. Am J Clin Nutr. 2008;88(5):1364–1370.
   PubMed Web of Science ®Google Scholar
• Mitjavila MT, Fandos M, Salas-Salvadó J, et al. The Mediterranean diet improves the systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled, trial. Clin Nutr. 2013;32(2):172–178.
   PubMed Web of Science ®Google Scholar
• Scalfari A, Neuhaus A, Daumer M, et al. Age and disability accumulation in multiple sclerosis. Neurology. 2011;77(13):1246–1252.
   PubMed Web of Science ®Google Scholar
• Morel A, Bijak M, Niwald M, et al. Markers of oxidative/nitrative damage of plasma proteins correlated with EDSS and BDI scores in patients with secondary progressive multiple sclerosis. Redox Rep. 2017;22(6):547–555.
   PubMed Web of Science ®Google Scholar
• Adamczyk-Sowa M, Pierzchala K, Sowa P, et al. Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol. 2014;65(4):543–550.
   PubMed Web of Science ®Google Scholar
• Gironi M, Borgiani B, Mariani E, et al. Oxidative stress is differentially present in multiple sclerosis courses, early evident, and unrelated to treatment. J Immunol Res. 2014;2014:1.
   Google Scholar
• Odinak MM, Bisaga GN, Zarubina IV. [New approaches to antioxidant therapy in multiple sclerosis]. Zhurnal Nevrol i psikhiatrii Im SS Korsakova. 2002;Suppl:72–75.
   Google Scholar
• Liu Y, Zhu B, Wang X, et al. Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003;139(1–2):27–35.
   PubMed Web of Science ®Google Scholar
• Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010;33(8):1061–1067.
   PubMed Web of Science ®Google Scholar
• Filler K, Lyon D, Bennett J, et al. Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clin. 2014;1:12–23.
   PubMedGoogle Scholar
• Katarina V, Gordana T, Svetlana MD, et al. Oxidative stress and neuroinflammation should be both considered in the occurrence of fatigue and depression in multiple sclerosis. Acta Neurol Belg. 2018. DOI: 10.1007/s13760-018-1015-8. [Epub ahead of print]
   PubMedGoogle Scholar
• Costello F. Vision disturbances in multiple sclerosis. Semin Neurol. 2016;36(02):185–195.
   PubMedGoogle Scholar
• Chhetri J, Gueven N. Targeting mitochondrial function to protect against vision loss. Expert Opin Ther Targets. 2016;20(6):721–736.
   PubMed Web of Science ®Google Scholar
• Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53(1):401–426.
   PubMed Web of Science ®Google Scholar
• Murphy R, O’Donoghue S, Counihan T, et al. Neuropsychiatric syndromes of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2017;88(8):697–708.
   PubMed Web of Science ®Google Scholar
• Diaz-Olavarrieta C, Cummings JL, Velazquez J, et al. Neuropsychiatric manifestations of multiple sclerosis. JNP. 1999;11(1):51–57.
   Google Scholar
• Wallace DC. A mitochondrial etiology of neuropsychiatric disorders. JAMA Psychiatry. 2017;74(9):863.
   PubMed Web of Science ®Google Scholar
• Pei L, Wallace DC. Mitochondrial etiology of neuropsychiatric disorders. Biol Psychiatry. 2018;83(9):722–730.
   PubMed Web of Science ®Google Scholar
• Jongen PJ, Ter Horst AT, Brands AM. Cognitive impairment in multiple sclerosis. Minerva Med. 2012;103(2):73–96.
   PubMed Web of Science ®Google Scholar
• Finsterer J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand. 2006;114(4):217–238.
   PubMed Web of Science ®Google Scholar
• Finsterer J. Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci. 2008;272(1–2):20–33.
   PubMed Web of Science ®Google Scholar
• Finsterer J. Cognitive dysfunction in mitochondrial disorders. Acta Neurol Scand. 2012;126(1):1–11.
   PubMed Web of Science ®Google Scholar
• Hughes AJ. Glutathione as a predictor of neuropsychological impairment in patients with relapsing remitting, secondary progressive, and primary progressive multiple sclerosis, 2014. Available from: https://pdfs.semanticscholar.org/1276/37c6dca288abbab286f4fa680f369a226e4f.pdf
   Google Scholar
• Revel F, Gilbert T, Roche S, et al. Influence of oxidative stress biomarkers on cognitive decline. JAD. 2015;45(2):553–560.
   Google Scholar
• Stanika RI, Pivovarova NB, Brantner CA, et al. Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Proc Natl Acad Sci USA. 2009;106(24):9854–9859.
   PubMed Web of Science ®Google Scholar
• Dong X, Wang Y, Qin Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30(4):379–387.
   PubMed Web of Science ®Google Scholar
• Bondy SC, LeBel CP. The relationship between excitotoxicity and oxidative stress in the central nervous system. Free Radic Biol Med. 1993;14(6):633–642.
   PubMed Web of Science ®Google Scholar
• Lindqvist D, Fernström J, Grudet C, et al. Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity. Transl Psychiatry. 2016;6(12):e971–e971.
   PubMed Web of Science ®Google Scholar
• Spiers JG, Chen H-J, Sernia C, et al. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci. 2014;8:456.
   PubMed Web of Science ®Google Scholar
• Kobayashi N, Machida T, Takahashi T, et al. Elevation by oxidative stress and aging of hypothalamic-pituitary-adrenal activity in rats and its prevention by vitamin E. J Clin Biochem Nutr. 2009;45(2):207–213.
   PubMed Web of Science ®Google Scholar
• Mokry LE, Ross S, Timpson NJ, et al. Obesity and multiple sclerosis: a Mendelian randomization study. PLOS Med. 2016;13(6):e1002053.
   PubMed Web of Science ®Google Scholar
• Langer-Gould A, Brara SM, Beaber BE, et al. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80(6):548–552.
   PubMed Web of Science ®Google Scholar
• Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752–1761.
   PubMed Web of Science ®Google Scholar
• Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract. 2013;7(5):e330–41 [cited 2019 May 26]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24455761
   PubMed Web of Science ®Google Scholar
• Wandinger K, Jabs W, Siekhaus A, et al. Association between clinical disease activity and Epstein–Barr virus reactivation in MS. Neurology. 2000;55(2):178–184.
   PubMed Web of Science ®Google Scholar
• Bray PF, Bloomer LC, Salmon VC, et al. Epstein–Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol. 1983;40(7):406–408.
   PubMedGoogle Scholar
• Lassoued S, Ben Ameur R, Ayadi W, et al. Epstein–Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines. Mol Cell Biochem. 2008;313(1–2):179–186.
   PubMed Web of Science ®Google Scholar
• Chen X, Kamranvar SA, Masucci MG. Oxidative stress enables Epstein–Barr virus-induced B-cell transformation by posttranscriptional regulation of viral and cellular growth-promoting factors. Oncogene. 2016;35(29):3807–3816.
   PubMed Web of Science ®Google Scholar
• Pormohammad A, Azimi T, Falah F, et al. Relationship of human herpes virus 6 and multiple sclerosis: a systematic review and meta-analysis. J Cell Physiol. 2018;233(4):2850–2862.
   PubMed Web of Science ®Google Scholar
• Berti R, Soldan SS, Akhyani N, et al. Extended observations on the association of HHV-6 and multiple sclerosis. J Neurovirol. 2000;6(Suppl 2):S85–S8 7.
   PubMedGoogle Scholar
• Sebastiano M, Chastel O, de Thoisy B, et al. Oxidative stress favours herpes virus infection in vertebrates: a meta-analysis. Curr Zool. 2016;62(4):325–332.
   PubMed Web of Science ®Google Scholar
• Costantini D, Seeber PA, Soilemetzidou S-E, et al. Physiological costs of infection: herpesvirus replication is linked to blood oxidative stress in equids. Sci Rep. 2018;8(1):10347.
   PubMedGoogle Scholar
• Isik B, Ceylan A, Isik R. Oxidative stress in smokers and non-smokers. Inhal Toxicol. 2007;19(9):767–769.
   PubMed Web of Science ®Google Scholar
• Ozguner F, Koyu A, Cesur G. Active smoking causes oxidative stress and decreases blood melatonin levels. Toxicol Indus Health. 2005;21(10):21–26.
   PubMedGoogle Scholar
• Bahar M, Ashtari F, Aghaei M, et al. Mycoplasma pneumonia seroposivity in Iranian patients with relapsing-remitting multiple sclerosis: a randomized case-control study. J Pak Med Assoc. 2012;62(3 Suppl 2):S6–S8.
   PubMed Web of Science ®Google Scholar
• Kariya C, Chu HW, Huang J, et al. Mycoplasma pneumoniae infection and environmental tobacco smoke inhibit lung glutathione adaptive responses and increase oxidative stress. Infect Immun. 2008;76(10):4455–4462.
   PubMed Web of Science ®Google Scholar
• Lasemi R, Kundi M, Moghadam NB, et al. Vitamin K2 in multiple sclerosis patients. Wien Klin Wochenschr. 2018;130(9–10):307–313.
   PubMed Web of Science ®Google Scholar
• Li J, Lin JC, Wang H, et al. Novel role of vitamin K in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci. 2003;23(13):5816–5826.
   PubMed Web of Science ®Google Scholar
• Sanna V, Di Giacomo A, La Cava A, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest. 2003;111(2):241–250.
   PubMed Web of Science ®Google Scholar
• De Rosa V, Procaccini C, Calì G, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26(2):241–255.
   PubMed Web of Science ®Google Scholar
• De Rosa V, Procaccini C, La CA, et al. Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. J Clin Invest. 2006;116(2):447–455.
   PubMed Web of Science ®Google Scholar
• Blanca AJ, Ruiz-Armenta MV, Zambrano S, et al. Leptin induces oxidative stress through activation of NADPH oxidase in renal tubular cells: antioxidant effect of l-carnitine. J Cell Biochem. 2016;117(10):2281–2288.
   PubMed Web of Science ®Google Scholar
• Shiryaev SA, Remacle AG, Savinov AY, et al. Inflammatory proprotein convertase–matrix metalloproteinase proteolytic pathway in antigen-presenting cells as a step to autoimmune multiple sclerosis. J Biol Chem. 2009;284(44):30615–30626 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19726693
   PubMed Web of Science ®Google Scholar
• Shiryaev SA, Savinov AY, Cieplak P, et al. Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. PLoS One. 2009;4(3):e4952 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19300513
   PubMed Web of Science ®Google Scholar
• Nelson KK, Melendez JA. Mitochondrial redox control of matrix metalloproteinases. Free Radic Biol Med. 2004;37(6):768–784 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15304253
   PubMed Web of Science ®Google Scholar
• Svineng G, Ravuri C, Rikardsen O, et al. The role of reactive oxygen species in integrin and matrix metalloproteinase expression and function. Connect Tissue Res. 2008;49(3–4):197–202 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18661342
   PubMed Web of Science ®Google Scholar
• Mori K, Uchida T, Yoshie T, et al. A mitochondrial ROS pathway controls matrix metalloproteinase 9 levels and invasive properties in RAS‐activated cancer cells. FEBS J. 2019;286(3):459–478 [cited 2019 Jul 4]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/febs.14671
   PubMed Web of Science ®Google Scholar
• Woo C-H, Lim J-H, Kim J-H. Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. J Immunol. 2004;173(11):6973–6980 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15557194
   PubMed Web of Science ®Google Scholar
• Grimm T, Schäfer A, Högger P. Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Free Radic Biol Med. 2004;36(6):811–822 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14990359
   PubMed Web of Science ®Google Scholar
• Castro MM, Rizzi E, Rodrigues GJ, et al. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med. 2009;46(9):1298–1307 [cited 2019 Jul 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19248829
   PubMed Web of Science ®Google Scholar
• Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6(1):28484 [cited 2019 Jul 6]. Available from: http://www.nature.com/articles/srep28484
   PubMed Web of Science ®Google Scholar
• Cekanaviciute E, Yoo BB, Runia TF, et al. Correction for ‘Gut’ bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci USA. 2017;10:10713–10718 [cited 2019 Jul 6]. Available from: www.pnas.org/cgi/doi/10.1073/pnas.1716911114www.pnas.org
   Google Scholar
• Luca M, Di Mauro M, Di Mauro M, et al. Gut microbiota in Alzheimer’s disease, depression, and type 2 diabetes mellitus: the role of oxidative stress. Oxid Med Cell Longev. 2019;2019:1–10 [cited 2019 Jun 16]. Available from: https://www.hindawi.com/journals/omcl/2019/4730539/
   Web of Science ®Google Scholar
• Campbell CL, Yu R, Li F, et al. Modulation of fat metabolism and gut microbiota by resveratrol on high-fat diet-induced obese mice. DMSO. 2019;12:97–107 [cited 2019 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30655683
   Google Scholar
• Zhao L, Zhang Q, Ma W, et al. A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. Food Funct. 2017;8(12):4644–4656 [cited 2019 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29152632
   PubMed Web of Science ®Google Scholar
• Yang C, Deng Q, Xu J, et al. Sinapic acid and resveratrol alleviate oxidative stress with modulation of gut microbiota in high-fat diet-fed rats. Food Res Int. 2019;116:1202–1211 [cited 2019 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30716907
   PubMed Web of Science ®Google Scholar
• Xu P, Wang J, Hong F, et al. Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res. 2017;62(4):e12399 [cited 2019 Jun 16]. Available from: http://doi.wiley.com/10.1111/jpi.12399
   Web of Science ®Google Scholar
• Qiao Y, Sun J, Xia S, et al. Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct. 2014;5(6):1241 [cited 2019 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24722352
   PubMed Web of Science ®Google Scholar
• Duquette P, Pleines J, Girard M, et al. The increased susceptibility of women to multiple sclerosis. Can J Neurol Sci. 1992;19(4):466–471.
   PubMed Web of Science ®Google Scholar
• Koch-Henriksen N, Thygesen LC, Stenager E, et al. Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women. Neurology. 2018;90(22):e1954–e1963 [cited 2019 Jul 13]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29720546
   PubMed Web of Science ®Google Scholar
• Kurth F, Luders E, Sicotte NL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. NeuroImage Clin. 2014;4:454–460.
   PubMed Web of Science ®Google Scholar
• Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis. Arch Neurol. 2007;64(5):683.
   PubMed Web of Science ®Google Scholar
• Kadish I, Van Groen T. Low levels of estrogen significantly diminish axonal sprouting after entorhinal cortex lesions in the mouse. J Neurosci. 2002;22(10):4095–4102 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12019328
   PubMed Web of Science ®Google Scholar
• Kumar S, Patel R, Moore S, et al. Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol Dis. 2013;56:131–144.
   PubMed Web of Science ®Google Scholar
• Hirahara Y, Matsuda K-I, Gao W, et al. The localization and non-genomic function of the membrane-associated estrogen receptor in oligodendrocytes. Glia. 2009;57(2):153–165.
   PubMed Web of Science ®Google Scholar
• Cantarella G, Risuglia N, Lombardo G, et al. Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions. Cell Death Differ. 2004;11(5):503–511.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Cerghet M, Mullins C, et al. Comparison of in vivo and in vitro subcellular localization of estrogen receptors alpha and beta in oligodendrocytes. J Neurochem. 2004;89(3):674–684.
   PubMed Web of Science ®Google Scholar
• Offner H. Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. J Neurosci Res. 2004;78(5):603–624.
   PubMed Web of Science ®Google Scholar
• Luo Y, Xiao Q, Chao F, et al. 17β-estradiol replacement therapy protects myelin sheaths in the white matter of middle-aged female ovariectomized rats: a stereological study. Neurobiol Aging. 2016;47:139–148.
   PubMed Web of Science ®Google Scholar
• Collongues N, Patte-Mensah C, De Seze J, et al. Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics. Expert Rev Neurother. 2018;18(6):515–522.
   PubMed Web of Science ®Google Scholar
• Marin-Husstege M, Muggironi M, Raban D, et al. Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev Neurosci. 2004;26(2–4):245–254.
   PubMed Web of Science ®Google Scholar
• Yu H, Fei J, Chen X, et al. Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein. Neurosci Lett. 2010;476(1):42–45.
   PubMed Web of Science ®Google Scholar
• Garay L, Deniselle MCG, Meyer M, et al. Protective effects of progesterone administration on axonal pathology in mice with experimental autoimmune encephalomyelitis. Brain Res. 2009;1283:177–185.
   PubMed Web of Science ®Google Scholar
• Garay L, Gonzalez Deniselle MC, Gierman L, et al. Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation. 2008;15(1):76–83.
   PubMed Web of Science ®Google Scholar
• Acs P, Kipp M, Norkute A, et al. 17β-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia. 2009;57(8):807–814.
   PubMed Web of Science ®Google Scholar
• Stocker S, Güttinger HR, Herth G. Exogenous testosterone differentially affects myelination and neurone soma sizes in the brain of canaries. Neuroreport. 1994;5(12):1449–1452.
   PubMed Web of Science ®Google Scholar
• Hussain R, Ghoumari AM, Bielecki B, et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain. 2013;136(1):132–146.
   PubMedGoogle Scholar
• Bielecki B, Mattern C, Ghoumari AM, et al. Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin. Proc Natl Acad Sci USA. 2016;113(51):14829–14834.
   PubMed Web of Science ®Google Scholar
• Gold SM, Voskuhl RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009;175:239–251.
   PubMed Web of Science ®Google Scholar
• Trenova AG, Slavov GS, Manova MG, Kostadinova II, et al. Female sex hormones and cytokine secretion in women with multiple sclerosis. Neurol Res. 2013;35(1):95–99.
   PubMed Web of Science ®Google Scholar
• Correale J, Arias M, Gilmore W, et al. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol. 1998;161(7):3365–3374.
   PubMed Web of Science ®Google Scholar
• Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002;52(4):421–428 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12325070
   PubMed Web of Science ®Google Scholar
• Soldan SS, Retuerto AIA, Sicotte NL, et al. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003;171(11):6267–6274 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14634144
   PubMed Web of Science ®Google Scholar
• Garay L, Deniselle MCG, Lima A, et al. Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. J Steroid Biochem Mol Biol. 2007;107(3–5):228–237.
   PubMed Web of Science ®Google Scholar
• Yates MA, Li Y, Chlebeck P, et al. Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;220(1–2):136–139.
   PubMed Web of Science ®Google Scholar
• Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004;89(7):3313–3318.
   PubMed Web of Science ®Google Scholar
• Gold SM, Chalifoux S, Giesser BS, et al. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J Neuroinflammation. 2008;5(1):32.
   PubMedGoogle Scholar
• Massa MG, David C, Jörg S, et al. Testosterone differentially affects T cells and neurons in murine and human models of neuroinflammation and neurodegeneration. Am J Pathol. 2017;187(7):1613–1622.
   PubMed Web of Science ®Google Scholar
• Zlotnik A, Gruenbaum BF, Mohar B, et al. The effects of estrogen and progesterone on blood glutamate levels: evidence from changes of blood glutamate levels during the menstrual cycle in women. Biol Reprod. 2011;84(3):581–586.
   PubMed Web of Science ®Google Scholar
• Gottlieb M, Wang Y, Teichberg VI. Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem. 2003;87(1):119–126.
   PubMed Web of Science ®Google Scholar
• Sribnick EA, Del Re AM, Ray SK, et al. Estrogen attenuates glutamate-induced cell death by inhibiting Ca influx through L-type voltage-gated Ca channels. Brain Res. 2009;1276:159–170 [cited 2019 Jul 7]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0006899309007744
   PubMed Web of Science ®Google Scholar
• Young E, Korszun A. Sex, trauma, stress hormones and depression. Mol Psychiatry. 2010;15(1):23–28.
   PubMed Web of Science ®Google Scholar
• Lee YJ, Lee EB, Kwon YE, et al. Effect of estrogen on the expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and tissue inhibitor of metalloproternase-1 in osteoarthritis chondrocytes. Rheumatol Int. 2003;23(6):282–288 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12684836
   PubMed Web of Science ®Google Scholar
• Claassen H, Steffen R, Hassenpflug J, et al. 17β-estradiol reduces expression of MMP-1, -3, and -13 in human primary articular chondrocytes from female patients cultured in a three dimensional alginate system. Cell Tissue Res. 2010;342(2):283–293 [cited 2019 Jul 6]. Available from: http://link.springer.com/10.1007/s00441-010-1062-9
   PubMed Web of Science ®Google Scholar
• Lekontseva O, Jiang Y, Davidge ST. Estrogen replacement increases matrix metalloproteinase contribution to vasoconstriction in a rat model of menopause. J Hypertens. 2009;27(8):1602–1608 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19412129
   PubMed Web of Science ®Google Scholar
• Imada K, Ito A, Sato T, et al. Hormonal regulation of matrix metalloproteinase 9/gelatinase B gene expression in rabbit uterine cervical fibroblasts. Biol Reprod. 1997;56(3):575–580 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9046999
   PubMed Web of Science ®Google Scholar
• Sandyk R. Estrogen’s impact on cognitive functions in multiple sclerosis. Int J Neurosci. 1996;86(1–2):23–31.
   PubMed Web of Science ®Google Scholar
• Hatami H, Babri S, Mirzaei F. Intrahippocampal administration of Vitamin C and progesterone attenuates spatial earning and memory impairments in multiple sclerosis rats. Anim Res Int. 2015;12(1):2097–2106.
   Google Scholar
• Bove R, Musallam A, Healy B, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler. 2014;20(12):1584–1592.
   PubMed Web of Science ®Google Scholar
• Voskuhl RR, Wang H, Wu TCJ, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(1):35–46.
   PubMed Web of Science ®Google Scholar
• Kim S, Liva SM, Dalal MA, et al. Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology. 1999;52(6):1230–1238.
   PubMed Web of Science ®Google Scholar
• Naci H, Fleurence R, Birt J, et al. Economic burden of multiple sclerosis. Pharmacoeconomics. 2010;28(5):363–379 [cited 2019 Jul 6]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20402540
   PubMed Web of Science ®Google Scholar
• Ricca C, Aillon A, Bergandi L, et al. Vitamin D receptor is necessary for mitochondrial function and cell health. Int J Mol Sci. 2018;19(6).
   Web of Science ®Google Scholar
• Wimalawansa SJ. Vitamin D deficiency: effects on oxidative stress, epigenetics, gene regulation, and aging. Biology (Basel). 2019;8(2):30 [cited 2019 Jul 11]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31083546
   PubMed Web of Science ®Google Scholar
• Tarbali S, Khezri S. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination. Iran J Basic Med Sci. 2006;(19):80–88 [cited 2019 Jul 9]. Available from: https://pdfs.semanticscholar.org/78a4/716b06b0253ad56b062863f4ddc1435f7fe3.pdf
   Google Scholar
• Kouchaki E, Afarini M, Abolhassani J, et al. High-dose ω-3 fatty acid plus vitamin D3 supplementation affects clinical symptoms and metabolic status of patients with multiple sclerosis: a randomized controlled clinical trial. J Nutr. 2018;148(8):1380–1386 [cited 2019 Jul 11]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29982544
   PubMed Web of Science ®Google Scholar
• Ma R, Gu Y, Zhao S, et al. Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies. Am J Physiol Endocrinol Metab. 2012;303(7):E928–E9 35.
   PubMed Web of Science ®Google Scholar
• Mackawy AMH, Al-Ayed BM, Al-Rashidi BM. Vitamin D deficiency and its association with thyroid disease. IJHS. 2013;7(3):267–275.
   Google Scholar
• Kivity S, Agmon-Levin N, Zisappl M, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol. 2011;8(3):243–247 [cited 2019 Jul 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21278761
   PubMed Web of Science ®Google Scholar
• Shin DY, Kim KJ, Kim D, et al. Low serum vitamin D is associated with anti-thyroid peroxidase antibody in autoimmune thyroiditis. Yonsei Med J. 2014;55(2):476 [cited 2019 Jul 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24532520
   PubMed Web of Science ®Google Scholar
• Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012;166(5):765–778.
   PubMed Web of Science ®Google Scholar
• Jukic AMZ, Steiner AZ, Baird DD. Lower plasma 25-hydroxyvitamin D is associated with irregular menstrual cycles in a cross-sectional study. Reprod Biol Endocrinol. 2015;13(1):20. Mar
   PubMedGoogle Scholar
• Spanier JA, Nashold FE, Mayne CG, et al. Vitamin D and estrogen synergy in Vdr-expressing CD4+ T cells is essential to induce Helios + FoxP3+ T cells and prevent autoimmune demyelinating disease. J Neuroimmunol. 2015;286:48–58.
   PubMed Web of Science ®Google Scholar
• Hayes CE, Nashold FE, Spach KM, et al. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J Immunol. 2017 [cited 2019 Jul 12]. Available from: http://www.jimmunol.org/content/183/6/3672
   Google Scholar
• Tak YJ, Lee JG, Kim YJ, et al. Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study. Asian J Androl. 2015;17(2):324–328.
   PubMed Web of Science ®Google Scholar
• Wang N, Han B, Li Q, et al. Vitamin D is associated with testosterone and hypogonadism in Chinese men: results from a cross-sectional SPECT-China study. Reprod Biol Endocrinol. 2015;13(1):74.
   PubMedGoogle Scholar
• Pilz S, Frisch S, Koertke H, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2011;43(03):223–225.
   PubMedGoogle Scholar
• Munger KL, Åivo J, Hongell K, et al. Vitamin D Status During Pregnancy and Risk of Multiple Sclerosis in Offspring of Women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515 [cited 2019 Jul 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26953778
   PubMed Web of Science ®Google Scholar
• Menzies KJ, Robinson BH, Hood DA. Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects. Am J Physiol Physiol. 2009;296(2):C355–C362.
   PubMed Web of Science ®Google Scholar
• Karbownik-Lewińska M, Kokoszko-Bilska A. Oxidative damage to macromolecules in the thyroid: experimental evidence. Thyroid Res. 2012;5(1):25.
   PubMedGoogle Scholar
• Villanueva I, Alva-Sánchez C, Pacheco-Rosado J. The role of thyroid hormones as inductors of oxidative stress and neurodegeneration. Oxid Med Cell Longev. 2013;2013:218145 [cited 2019 Jul 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24386502
   PubMed Web of Science ®Google Scholar
• Toro-Urrego N, Garcia-Segura LM, Echeverria V, et al. Testosterone protects mitochondrial function and regulates neuroglobin expression in astrocytic cells exposed to glucose deprivation. Front Aging Neurosci. 2016;8:152.
   PubMed Web of Science ®Google Scholar
• Túnez I, Feijóo M, Collado JA, et al. Effect of testosterone on oxidative stress and cell damage induced by 3-nitropropionic acid in striatum of ovariectomized rats. Life Sci. 2007;80(13):1221–1227.
   PubMed Web of Science ®Google Scholar
• Marin DP, Bolin AP, dos Santos R de CM, et al. Testosterone suppresses oxidative stress in human neutrophils. Cell Biochem Funct. 2010;28(5):394–402.
   PubMed Web of Science ®Google Scholar
• Berco M, Bhavnani BR. Differential neuroprotective effects of equine estrogens against oxidized low density lipoprotein-induced neuronal cell death. J Soc Gynecol Investig. 8(4):245–254.
   PubMedGoogle Scholar
• Borrás C, Gambini J, López-Grueso R, et al. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim Biophys Acta Mol Basis Dis. 2010;1802(1):205–211.
   PubMed Web of Science ®Google Scholar
• Malins DC, Polissar NL, Gunselman SJ, et al. Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage. Proc Natl Acad Sci USA. 1996;93(6):2557–2563.
   PubMed Web of Science ®Google Scholar
• Simpkins JW, Yang S-H, Sarkar SN, et al. Estrogen actions on mitochondria–physiological and pathological implications. Mol Cell Endocrinol. 2008;290(1–2):51–59.
   PubMed Web of Science ®Google Scholar
• Klinge CM. Estrogenic control of mitochondrial function and biogenesis. J Cell Biochem. 2008;105(6):1342–1351.
   PubMed Web of Science ®Google Scholar
• Subramanian M, Pusphendran CK, Tarachand U, et al. Gestation confers temporary resistance to peroxidation in the maternal rat brain. Neurosci Lett. 1993;155(2):151–154.
   PubMed Web of Science ®Google Scholar
• Yuan X-H, Fan Y-Y, Yang C-R, et al. Progesterone amplifies oxidative stress signal and promotes NO production via H2O2 in mouse kidney arterial endothelial cells. J Steroid Biochem Mol Biol. 2016;155(Pt A):104–111.
   PubMedGoogle Scholar
• Saran S, Gupta BS, Philip R, et al. Effect of hypothyroidism on female reproductive hormones. Indian J Endocr Metab. 2016;20(1):108–113.
   PubMedGoogle Scholar
• Vissenberg R, Manders VD, Mastenbroek S, et al. Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction. Hum Reprod Update. 2015;21(3):378–387 [cited 2019 Jul 6]. Available from: http://academic.oup.com/humupd/article/21/3/378/676494/Pathophysiological-aspects-of-thyroid-hormone
   PubMed Web of Science ®Google Scholar
• Meikle AW. The interrelationships between thyroid dysfunction and hypogonadism in men and boys. Thyroid. 2004;14(Suppl 1):17–25.
   PubMedGoogle Scholar
• Kular L, Liu Y, Ruhrmann S, et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun. 2018;9(1):2397.
   PubMedGoogle Scholar
• Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 2009;5(2):e1000369.
   PubMed Web of Science ®Google Scholar
• Cree BAC. Multiple sclerosis genetics. In: Handbook of clinical neurology. 2014. p. 193–209. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24507519
   Google Scholar
• Sarchielli P, Greco L, Stipa A, et al. Brain-derived neurotrophic factor in patients with multiple sclerosis. J Neuroimmunol. 2002;132(1–2):180–188.
   PubMed Web of Science ®Google Scholar
• Wens I, Keytsman C, Deckx N, et al. Brain derived neurotrophic factor in multiple sclerosis: effect of 24 weeks endurance and resistance training. Eur J Neurol. 2016;23(6):1028–1035.
   PubMed Web of Science ®Google Scholar
• Nociti V, Santoro M, Quaranta D, et al. BDNF rs6265 polymorphism methylation in multiple sclerosis: a possible marker of disease progression. PLoS One. 2018;13(10):e0206140.
   PubMed Web of Science ®Google Scholar
• Pozzi F, Aloe L, Frajese G, et al. Vitamin D (calcifediol) supplementation modulates NGF and BDNF and improves memory function in postmenopausal women: a pilot study. Res Endocrinol. 2013;2013:1–11.
   Google Scholar
• Karege F, Perret G, Bondolfi G, et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109(2):143–148.
   PubMed Web of Science ®Google Scholar
• Schreibelt G, van Horssen J, van Rossum S, et al. Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res Rev. 2007;56(2):322–330.
   PubMedGoogle Scholar
• van Horssen J, Schreibelt G, Drexhage J, et al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med. 2008;45(12):1729–1737.
   PubMed Web of Science ®Google Scholar
• Sohrabji F, Miranda RC, Toran-Allerand CD. Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92(24):11110–11114.
   PubMed Web of Science ®Google Scholar
• Singh M, Meyer EM, Simpkins JW. The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology. 1995;136(5):2320–2324.
   PubMed Web of Science ®Google Scholar
• Solum DT, Handa RJ. Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci. 2002;22(7):2650–2659.
   PubMed Web of Science ®Google Scholar
• Singh M, Su C. Progesterone, brain-derived neurotrophic factor and neuroprotection. Neuroscience. 2013;239:84–91.
   PubMed Web of Science ®Google Scholar
• Ebrahimzadeh M, Shahabi P, Mohaddes G, et al. Effect of testosterone on memory and BDNF levels of hippocampus in gonadectomized diabetic rats. Biosci Biotech Res Asia. 2015;12(3):2433–2440.
   Google Scholar
• Nejati A, Shoja Z, Shahmahmoodi S, et al. EBV and vitamin D status in relapsing-remitting multiple sclerosis patients with a unique cytokine signature. Med Microbiol Immunol. 2016;205(2):143–154.
   PubMed Web of Science ®Google Scholar
• Røsjø E, Lossius A, Abdelmagid N, et al. Effect of high-dose vitamin D3 supplementation on antibody responses against Epstein–Barr virus in relapsing-remitting multiple sclerosis. Mult Scler. 2017;23(3):395–402.
   PubMed Web of Science ®Google Scholar
• Rolf L, Muris A-H, Mathias A, et al. Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis. Mult Scler. 2018;24(10):1280–1287.
   PubMed Web of Science ®Google Scholar
• Mikirova N, Hunninghake R. Effect of high dose vitamin C on Epstein–Barr viral infection. Med Sci Monit. 2014;20:725–732.
   PubMed Web of Science ®Google Scholar
• Citterio A, L, Mantia L, Ciucci G, Candelise L, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;(4):CD001331.
   PubMedGoogle Scholar
• Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009;29(12):1867–1878. http://dx.doi.org/101038/jcbfm2009180. 2009.
   Google Scholar
• Tsai C-C, Kao S-C, Cheng C-Y, et al. Oxidative stress change by systemic corticosteroid treatment among patients having active graves ophthalmopathy. Arch Ophthalmol. 2007;125(12):1652.
   PubMedGoogle Scholar
• Disanto G, Morahan JM, Barnett MH, et al. The evidence for a role of B cells in multiple sclerosis. Neurology. 2012;78(11):823–832.
   PubMed Web of Science ®Google Scholar
• Rolf L, Muris A-H, Hupperts R, et al. Illuminating vitamin D effects on B cells: the multiple sclerosis perspective. Immunology. 2016;147(3):275–284.
   PubMed Web of Science ®Google Scholar
• Gollapudi S, Gupta S. Reversal of oxidative stress-induced apoptosis in T and B lymphocytes by coenzyme Q10 (CoQ10). Am J Clin Exp Immunol. 2016;5(2):41–47.
   PubMed Web of Science ®Google Scholar
• Parnell GP, Booth DR. The multiple sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities. Front Immunol. 2017;8:425.
   PubMed Web of Science ®Google Scholar
• Fetisova E, Chernyak B, Korshunova G, et al. Mitochondria-targeted antioxidants as a prospective therapeutic strategy for multiple sclerosis. Curr Med Chem. 2017;24(19):2086–2114.
   PubMed Web of Science ®Google Scholar
• Carlson NG, Rose JW. Antioxidants in multiple sclerosis. CNS Drugs. 2006;20(6):433–441.
   PubMed Web of Science ®Google Scholar
• Mclaughlin L, Clarke L, Khalilidehkordi E, et al. Vitamin D in the treatment of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatr. 2017;88(5):e1.95–e1.
   Web of Science ®Google Scholar
• Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77(17):1611–1618.
   PubMed Web of Science ®Google Scholar
• Kampman MT, Steffensen LH, Mellgren SI, et al. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler. 2012;18(8):1144–1151.
   PubMed Web of Science ®Google Scholar
• Hernán MA, Hohol MJ, Olek MJ, et al. Oral contraceptives and the incidence of multiple sclerosis. Neurology. 2000;55(6):848–854.
   PubMed Web of Science ®Google Scholar
• Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451–1457.
   PubMed Web of Science ®Google Scholar
• Sanoobar M, Dehghan P, Khalili M, et al. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial. Nutr Neurosci. 2016;19(3):138–143.
   PubMed Web of Science ®Google Scholar
• Sanoobar M, Eghtesadi S, Azimi A, et al. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial. Nutr Neurosci. 2015;18(4):169–176.
   PubMed Web of Science ®Google Scholar
• Sanoobar M, Eghtesadi S, Azimi A, et al. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing–remitting multiple sclerosis. Int J Neurosci. 2013;123(11):776–782.
   PubMed Web of Science ®Google Scholar
• Adamczyk-Sowa M, Pierzchala K, Sowa P, et al. Melatonin acts as antioxidant and improves sleep in MS patients. Neurochem Res. 2014;39(8):1585–1593.
   PubMed Web of Science ®Google Scholar
• Liao W-C, Chiu M-J, Landis CA. A warm footbath before bedtime and sleep in older Taiwanese with sleep disturbance. Res Nurs Health. 2008;31(5):514–528.
   PubMed Web of Science ®Google Scholar
• Mindell JA, Telofski LS, Wiegand B, et al. A nightly bedtime routine: impact on sleep in young children and maternal mood. Sleep. 2009;32(5):599–606.
   PubMed Web of Science ®Google Scholar
• Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Mult Scler. 2008;14(1):129–135.
   PubMed Web of Science ®Google Scholar
• Pilutti LA, Greenlee TA, Motl RW, et al. Effects of exercise training on fatigue in multiple sclerosis. Psychosom Med. 2013;75(6):575–580.
   PubMed Web of Science ®Google Scholar
• Marck CH, Hadgkiss EJ, Weiland TJ, et al. Physical activity and associated levels of disability and quality of life in people with multiple sclerosis: a large international survey. BMC Neurol. 2014;14(1):143 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25016312
   PubMed Web of Science ®Google Scholar
• Dorans KS, Massa J, Chitnis T, et al. Physical activity and the incidence of multiple sclerosis. Neurology. 2016;87(17):1770–1776.
   PubMed Web of Science ®Google Scholar
• Weiland TJ, Hadgkiss EJ, Jelinek GA, et al. The association of alcohol consumption and smoking with quality of life, disability and disease activity in an international sample of people with multiple sclerosis. J Neurol Sci. 2014;336(1–2):211–219 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24290614
   PubMed Web of Science ®Google Scholar
• Fitzgerald KC, Tyry T, Salter A, et al. Diet quality is associated with disability and symptom severity in multiple sclerosis. Neurology. 2018;90(1):e1–11.
   PubMed Web of Science ®Google Scholar
• Ellenbroek JH, van Dijck L, Töns HA, et al. Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice. Am J Physiol Metab. 2014;306(5):E552–8 [cited 2019 Jun 23]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24398402
   PubMed Web of Science ®Google Scholar
• Paoli A. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health. 2014;11(2):2092–2107 [cited 2019 Jun 23]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24557522
   PubMed Web of Science ®Google Scholar
• Jelinek GA, Hadgkiss EJ, Weiland TJ, et al. Association of fish consumption and omega 3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis. Int J Neurosci. 2013;123(11):792–801 [cited 2019 Jul 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23713615
   PubMed Web of Science ®Google Scholar