Update on riboflavin and multiple sclerosis: a systematic review

Document Type : Review Article

Authors

1 Abadan School of Medical Sciences, Abadan, Iran

2 Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran

3 Department of Nutrition, Faculty of Para-Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran

4 Food Security Research Center, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

5 Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran

6 Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran

7 Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran

8 Department of Pharmacology, School of Medicine, Western Sydney University, NSW, Australia

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Riboflavin plays an important role in myelin formation, and its deficiency is implicated as a risk factor for multiple sclerosis. Here, we systematically reviewed the literature concerning the health benefits of riboflavin on MS. The literature recorded within four main databases, including relevant clinical trials, experimental, and case-control studies from 1976 to 2017 were considered. Both human and animal studies were included for review, with no restrictions on age, gender, or ethnicity.  Experimental studies demonstrated that riboflavin deficiency triggers neurologic abnormalities related to peripheral neuropathies such as demyelinating neuropathy. Moreover, randomized controlled trials (RCT) and case-control studies in which MS patients received riboflavin supplementation or had higher dietary riboflavin intake showed improvements in neurological motor disability. Riboflavin is a cofactor of xanthine oxidase and its deficiency exacerbates low uric acid caused by high copper levels, leading to myelin degeneration. The vitamin additionally plays a significant role in the normal functioning of glutathione reductase (GR) as an antioxidant enzyme, and conditions of riboflavin deficiency lead to oxidative damage. Riboflavin promotes the gene and protein levels of brain-derived neurotrophic factor (BDNF) in the CNS of an animal model of MS, suggesting that BDNF mediates the beneficial effect of riboflavin on neurological motor disability. Research to date generally supports the role of riboflavin in MS outcomes. However, further observational and interventional studies on human populations are warranted to validate the effects of riboflavin.

Keywords

References

1. Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol 2014; 122:15-58.
2. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83:1022-1024.
3. Pappas DJ, Oksenberg JR. Multiple sclerosis pharmacogenomics: maximizing efficacy of therapy. Neurology 2010; 74:S62-69.
4. Harrirchian MH, Mohammadzadeh Honarvar N, Koohdani F, Bitarafan S, Siassi F, Jafarirad S, et al. The effect of vitamin A supplementation on disease progression, cytokine levels and gene expression in multiple sclerotic patients: study protocol for a randomized controlled trial. Acta Med Iran 2014; 52:94-100.
5. Mazur-Bialy AI, Buchala B, Plytycz B. Riboflavin deprivation inhibits macrophage viability and activity - a study on the RAW 264.7 cell line. Br J Nutr 2013; 110:509-514.
6. Johnson S. The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis. Med Hypotheses 2000; 55:239-241.
7. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr 2003; 77:1352-1360.
8. LeBlanc JG, Rutten G, Bruinenberg P, Sesma F, de Giori GS, Smid EJ. A novel dairy product fermented with Propionibacterium freudenreichii improves the riboflavin status of deficient rats. Nutrition 2006; 22:645-651.
9. Naghashpour M, Nematpour S, Haghighizadeh MH. Dietary, anthropometric, biochemical and psychiatric indices in shift work nurses. Food Nutr Sci J 2013; 4:1239-1246.
10. Naghashpour M, Amani R, Nutr R, Nematpour S, Haghighizadeh MH. Riboflavin status and its association with serum hs-CRP levels among clinical nurses with depression. J Am Coll Nutr 2011; 30:340-347.
11. Vafa MR, Karandish M, Mosavi SM, Alizadeh M, Salehi  MH, Maddah M. Evaluation of urinary riboflavin levels of primary School Children in Rafsanjan, Iran. J Biol Sci 2009; 9:389-391.
12. Naghashpour M, Majdinasab N, Shakerinejad G, Kouchak M, Haghighizadeh MH, Jarvandi F, et al. Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine. Int J Vitam Nutr Res 2013; 83:281-290.
13. Ogunleye AJ, Odutuga AA. The effect of riboflavin deficiency on cerebrum and cerebellum of developing rat brain. J Nutr Sci Vitaminol (Tokyo) 1989; 35:193-197.
14. Cai Z, Blumbergs PC, Finnie JW, Manavis J, Thompson PD. Selective vulnerability of peripheral nerves in avian riboflavin deficiency demyelinating polyneuropathy. Vet Pathol 2009; 46:88-96.
15. Johnson WD, Storts RW. Peripheral neuropathy associated with dietary riboflavin deficiency in the chicken. I. Light microscopic study. Vet Pathol 1988; 25:9-16.
16. Cai Z, Finnie JW, Blumbergs PC. Avian riboflavin deficiency: an acquired tomaculous neuropathy. Vet Pathol 2006; 43:780-781.
17. Wada Y, Kondo H, Itakura C. Peripheral neuropathy of dietary riboflavin deficiency in racing pigeons. J Vet Med Sci 1996; 58:161-163.
18. Jortner BS, Cherry J, Lidsky TI, Manetto C, Shell L. Peripheral neuropathy of dietary riboflavin deficiency in chickens. J Neuropathol Exp Neurol 1987; 46:544-555.
19. Cai Z, Blumbergs PC, Finnie JW, Manavis J, Thompson PD. Novel fibroblastic onion bulbs in a demyelinating avian peripheral neuropathy produced by riboflavin deficiency. Acta Neuropathol 2007; 114:187-194.
20. Allison T, Roncero I, Forsyth R, Coffman K, Le Pichon JB. Brown-vialetto-van laere syndrome as a mimic of neuroimmune disorders. J Child Neurol 2017:883073816689517.
21. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444-1452.
22. Kurtzke JF. A new scale for evaluating disability in multiple sclerosis. Neurology 1955; 5:580-583.
23. Bisaga GN, Odinak MM, Boĭko AN, Mel'nik IuB, Popova NF. Possibilities of treatment of multiple sclerosis exacerbations without corticosteroids: a role of metabolic and antioxidant therapy. Zh Nevrol Psikhiatr Im S S Korsakova 2011; 111:44-48.
24. Ghadirian P, Jain M, Ducic S, Shatenstein B, Morisset R. Nutritional factors in the aetiology of multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol 1998; 27:845-852.
25. Cai Z, Finnie JW, Blumbergs PC, Manavis J, Ghabriel MN, Thompson PD. Early paranodal myelin swellings (tomacula) in an avian riboflavin deficiency model of demyelinating neuropathy. Exp Neurol 2006; 198:65-71.
26. Norton WN, Daskal I, Savage HE, Seibert RA, Lane M. Effects of riboflavin deficiency on the ultrastructure of rat sciatic nerve fibers. Am J Pathol 1976; 85:651-660.
27. Toyosawa T, Suzuki M, Kodama K, Araki S. Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. Eur J Pharmacol 2004; 492:273-280.
28. Araki S, Suzuki M, Fujimoto M, Kimura M. Enhancement of resistance to bacterial infection in mice by vitamin B2. J Vet Med Sci 1995; 57:599-602.
29. Verdrengh M, Tarkowski A. Riboflavin in innate and acquired immune responses. Inflamm Res 2005; 54:390-393.
30. Wertman KF, Sypherd PS. The effects of riboflavin deficiency on phagocytosis and susceptibility to infection. J Immunol 1960; 85:511-515.
31. Pelliccione NJ, Karmali R, Rivlin RS, Pinto J. Effects of riboflavin deficiency upon prostaglandin biosynthesis in rat kidney. Prostaglandins Leukot Med  1985; 17:349–358.
32. Ashoori M, Saedisomeolia A. Riboflavin (vitamin B2) and oxidative stress: a review. Br J Nutr 2014; 111:1985-1991.
33. Vogel DY, Vereyken EJ, Glim JE, Heijnen PD, Moeton M, van der Valk P, et al. Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflamm 2013; 10:1-12.
34. Christophi GP, Panos M, Hudson CA, Christophi RL, Gruber RC, Mersich AT, et al. Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Lab Invest 2009; 89:742-759.
35. Naghashpour M, Amani R, Sarkaki A, Ghadiri A, Samarbafzadeh A, Jafarirad S, et al. Brain-derived neurotrophic and immunologic factors: beneficial effects of riboflavin on motor disability in murine model of multiple sclerosis. Iran J Basic Med Sci 2016; 19:439-448.
36. Murphy PG, Borthwick LA, Altares M, Gauldie J, Kaplan D, Richardson PM. Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur J Neurosci 2000; 12:1891-1899.
37. Naghashpour M, Amani R, Sarkaki A, Ghadiri A,  Samarbaf-Zadeh A, Jafarirad S, et al. Brain-derived neurotrophic factor in murine model of multiple sclerosis: beneficial effects of riboflavin on motor disability. Int J Vitam Nutr Res 2016; 19:439-448.
38. Manole A, Houlden H. Riboflavin transporter deficiency neuronopathy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al. editors. Gene Rev Seattle (WA)1993.
39. Chen L, Feng L, Jiang WD, Jiang J, Wu P, Zhao J, et al. Dietary riboflavin deficiency decreases immunity and antioxidant capacity, and changes tight junction proteins and related signaling molecules mRNA expression in the gills of young grass carp (Ctenopharyngodon idella). Fish Shellfish Immunol 2015; 45:307-320.
40. Sakurai T, Miyazawa S, Furuta S, Hashimoto T. Riboflavin deficiency and beta-oxidation systems in rat liver. Lipids 1982; 17:598-604.
41. Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 1999; 31:273-300.
42. Mulherin DM, Thurnham DI, Situnayake RD. Glutathione reductase activity, riboflavin status, and disease activity in rheumatoid arthritis. Ann Rheum Dis 1996; 55:837-840.
43. Hejazi E, Amani R, SharafodinZadeh N, Cheraghian B. Comparison of antioxidant status and vitamin D levels between multiple sclerosis patients and healthy matched subjects. Mult Scler Int 2014; 2014:539854.
44. Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact 2006; 163:94-112.
45. Azoulay D, Urshansky N, Karni A. Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection. J Neuroimmunol 2008; 195.
46. Benveniste EN, Whitaker JN, Gibbs DA, Sparacio SM, Butler JL. Human B cell growth factor enhances proliferation and glial fibrillary acidic protein gene expression in rat astrocytes. Int Immunol 1989; 1:219-228.
47. Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol 1990; 144:129-135.
48. Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH. IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 2000; 32:328-337.
49. Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol 1989; 19:689-694.
50. Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 2012; 8:1254-1266.
51. Cicek G, Schiltz E, Hess D, Staiger J, Brandsch R. Analysis of mitochondrial antigens reveals inner membrane succinate dehydrogenase flavoprotein subunit as autoantigen to antibodies in anti-M7 sera. Clin Exp Immunol 2002; 128:83-87.
52. Reese D, Shivapour ET, Wahls TL, Dudley-Javoroski SD, Shields R. Neuromuscular electrical stimulation and dietary interventions to reduce oxidative stress in a secondary progressive multiple sclerosis patient leads to marked gains in function: a case report. Cases J 2009; 2:7601.
53. Udhayabanu T, Manole A, Rajeshwari M, Varalakshmi P, Houlden H, Ashokkumar B. Riboflavin responsive mitochondrial dysfunction in neurodegenerative diseases. J Clin Med 2017; 6.
Iranian Journal of Basic Medical Sciences
Volume 20, Issue 9
September 2017
Pages 958-966

Files

Share

How to cite

Statistics