Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund’s adjuvant

Abstract

Background

The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund’s adjuvant (CFA) in rats.

Methods

Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21 days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500 mg/kg) or thiamine (150, 300 or 600 mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5 mg/kg day, po) was administered every three days.

Results

CFA induced long lasting mechanical allodynia and paw edema. Elevation of body temperature was observed for a short period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but partially inhibited mechanical allodynia. Riboflavin (500 mg/kg) and thiamine (600 mg/kg) exacerbated the anti-inflammatory activity of dexamethasone. Riboflavin, thiamine and dexamethasone reduced TNF-α and IL-6 production. The association of dexamethasone with thiamine induced greater inhibition of IL-6 production when compared with that induced by dexamethasone.

Conclusions

Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.

This is a preview of subscription content, access via your institution.

References

  1. [1]

    Cohen SN, Baron SE, Archer CB. British Association of Dermatologists and Royal College of General Practitioners: guidance on the diagnosis and clinical management of psoriasis. Clin Exp Dermatol 2012;37:13–8.

    PubMed  Article  PubMed Central  Google Scholar 

  2. [2]

    Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol 2015;25:103–13.

    PubMed  PubMed Central  Google Scholar 

  3. [3]

    Tayar JH, Suarez-Almazor ME. New understanding and approaches to treatment in rheumatoid arthritis. Br Med Bull 2010;94:201–14.

    PubMed  Article  PubMed Central  Google Scholar 

  4. [4]

    Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med 2013;368:1528–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. [5]

    Willis MA, Cohen JA. Fingolimod therapy for multiple sclerosis. Semin Neurol 2013;33:37–44.

    PubMed  Article  PubMed Central  Google Scholar 

  6. [6]

    Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2014;73:516–28.

    CAS  Article  Google Scholar 

  7. [7]

    Codreanu C, Damjanov N. Safety of biologics in rheumatoid arthritis: data from randomized controlled trials and registries. Biologics 2015;9:1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. [8]

    Jörg J, Metz F, Scharafinski H. Drug treatment of diabetic polyneuropathy with alpha-lipoic acid or vitamin B preparations. A clinical and neurophysiologic study. Nervenarzt 1988;59:36–44.

    PubMed  PubMed Central  Google Scholar 

  9. [9]

    Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. Br Med J 1999;318:1375–81.

    CAS  Article  Google Scholar 

  10. [10]

    Folkers K, Wolaniuk A, Vadhanavikit S. Enzymology of the response of the carpal tunnel syndrome to riboflavin and to combined riboflavin and pyridoxine. Proc Natl Acad Sci U S A 1984;81:7076–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. [11]

    Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhäupl KM, Arnold G. High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol 2004;11:475–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. [12]

    Condò M, Posar A, Arbizzani A, Parmeggiani A. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain 2009;10:361–5.

    PubMed  PubMed Central  Article  Google Scholar 

  13. [13]

    Goldberg H, Kede J, Ribeiro MG, Higino KS, Nunes CP, Nunes FP, et al. Safety and efficacy of a combination of dexamethasone plus B-vitamins in the treatment of inflammatory neuropathies. Rev Bras Med 2007;64:177–81.

    Google Scholar 

  14. [14]

    Goldberg H, Nunes CP, Cardoso CAF, Paoli F, Ribeiro MG, Higashi R, et al. Treatment of inflammatory neuropathy with dexamethasone plus B-vitamins: a clinical evaluation. Rev Bras Med 2009;66:169–73.

    Google Scholar 

  15. [15]

    Bartoszyk GD, Wild A. Antinociceptive effects of pyridoxine, thiamine, and cyanocobalamin in rats. Ann N Y Acad Sci 1990;585:473–6.

    Article  Google Scholar 

  16. [16]

    Zimmermann M, Bartoszyk GD, Bonke D, Jurna I, Wild A. Antinociceptive properties of pyridoxine. Neurophysiol Behav Find Ann N Y Acad Sci 1990;585:219–30.

    CAS  Article  Google Scholar 

  17. [17]

    França DS, Souza ALS, Almeida KR, Dolabella SS, Martinelli C, Coelho MM. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol 2001;421:157–64.

    PubMed  Article  PubMed Central  Google Scholar 

  18. [18]

    Bertollo CM, Oliveira ACP, Rocha LTS, Costa KA, Nascimento Jr. EB, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of riboflavin in different experimental models. Eur J Pharmacol 2006;547:184–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. [19]

    Rogovik AL, Vohra S, Goldman RD. Safety considerations and potential interactions of vitamins: should vitamins be considered drugs. Ann Pharmacother 2010;44:311–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. [20]

    Gordon CJ. Thermal biology of the laboratory rat. Physiol Behav 1990;47:963–91.

    CAS  Article  Google Scholar 

  21. [21]

    Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109–10.

    CAS  Article  Google Scholar 

  22. [22]

    Hegen M, Keith Jr. JC, Collins M, Nickerson-Nutter CL. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis 2008;67:1505–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. [23]

    Grubb BD, Birrell GJ, Mcqueen DS, Iggo A. The role of PGE2 in the sensitization of mechanoreceptors in normal and inflamed ankle joints of the rat. Exp Brain Res 1991;84:383–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. [24]

    Ferreira J, Campos MM, Pesquero JB, Araújo RC, Bader M, Calixto JB. Evidence for the participation of kinins in Freund’s adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice. Neuropharmacology 2001;41:1006–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. [25]

    Helyes Z, Szabó A, Németh J, Jakab B, Pintér E, Bánvölgyi A, et al. Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund’s adjuvant-induced chronic arthritis model in the rat. Arthritis Rheum 2004;50:1677–85.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. [26]

    Oliveira PG, Brenol CV, Edelweiss MI, Brenol JC, Petronilho F, Roesler R, et al. Effects of an antagonist of the bombesin/gastrin-releasing peptide receptor on complete Freund’s adjuvant-induced arthritis in rats. Peptides 2008;29:1726–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. [27]

    Chou LW, Wang J, Chang PL, Hsieh YL. Hyaluronan modulates accumulation of hypoxia-inducible factor-1 alpha, inducible nitric oxide synthase, and matrix metalloproteinase-3 in the synovium of rat adjuvant-induced arthritis model. Arthritis Res Ther 2011;13:R90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. [28]

    Lima MD, Quintans-Júnior LJ, De Santana WA, Martins Kaneto C, Pereira Soares MB, Villarreal CF. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur J Pharmacol 2012;699:112–7.

    Article  CAS  Google Scholar 

  29. [29]

    De Castro Costa M, De Sutter P, Gybels J, Van Hees J. Adjuvant-induced arthritis in rats: a possible animal model of chronic pain. Pain 1981;10:173–85.

    PubMed  Article  PubMed Central  Google Scholar 

  30. [30]

    Colpaert FC, Meert T, De Witte P, Schmitt P. Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat. Life Sci 1982;31:67–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. [31]

    Philippe L, Gegout-Pottie P, Guingamp C, Bordji K, Terlain B, Netter P, et al. Relations between functional, inflammatory, and degenerative parameters during adjuvant arthritis in rats. Am J Physiol 1997;273:R1550–1556.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. [32]

    Gegout P, Gillet P, Chevrier D, Guingamp C, Terlain B, Netter P. Characterization of zymosan-induced arthritis in the rat: effects on joint inflammation and cartilage metabolism. Life Sci 1994;55:321–6.

    Article  Google Scholar 

  33. [33]

    Wang ZB, Gan Q, Rupert RL, Zeng YM, Song XJ. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain 2005;114:266–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. [34]

    Moallem SA, Hosseinzadeh H, Farahi S. A study of acute and chronic anti-nociceptive and anti-inflammatory effects of thiamine in mice. Iran Biomed J 2008;12:173–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. [35]

    Song XS, Huang ZJ, Song XJ. Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology 2009;110:387–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. [36]

    Vocci FJ, Petty SK, Dewey WL. Antinociceptive action of the butyryl derivatives of cyclic guanosine 3′:5′-monophosphate. J Pharmacol Exp Ther 1978;207:892–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. [37]

    Abacioğlu N, Demir S, Cakici I, Tunçtan B, Kanzik I. Role of guanylyl cyclase activation via thiamine in suppressing chemically-induced writhing in mouse. Arzneimittelforschung 2000;50:554–8.

    PubMed  PubMed Central  Google Scholar 

  38. [38]

    Misra AL, Vadlamani NL, Pontani RB. Differential effects of opiates on the incorporation of [14C] thiamine in the central nervous system of the rat. Experientia 1977;15:372–4.

    Article  Google Scholar 

  39. [39]

    Plaitakis A, Nicklas WJ, Berl S. Thiamine deficiency: selective impairment of the cerebellar serotonergic system. Neurology 1978;28:691–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. [40]

    Mazur-Bialy AI, Majka A, Wojtas L, Kolaczkowska E, Plytycz B. Strain-specific effects of riboflavin supplementation on zymosan-induced peritonitis in C57BL/6J, BALB/c and CBA mice. Life Sci 2011;88:265–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. [41]

    Granados-Soto V, Terán-Rosales F, Rocha-González HI, Reyes-García G, Medina-Santillán R, Rodríguez-Silverio J, et al. Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol 2004;492:35–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. [42]

    Verdrengh M, Tarkowski A. Riboflavin in innate and acquired immune responses. Inflamm Res 2005;54:390–3.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. [43]

    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;492:273–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. [44]

    Toyosawa T, Suzuki M, Kodama K, Araki S. Potentiation by amino acid of the therapeutic effect of highly purified vitamin B2 in mice with lipopolysaccharide-induced shock. Eur J Pharmacol 2004;493:177–82.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. [45]

    Kodama K, Suzuki M, Toyosawa T, Araki S. Inhibitory mechanisms of highly purified vitamin B2 on the productions of proinflammatory cytokine and NO in endotoxin-induced shock in mice. Life Sci 2005;78:134–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. [46]

    Mal P, Dutta K, Bandyopadhyay D, Basu A, Khan R, Bishayi B. Azithromycin in combination with riboflavin decreases the severity of Staphylococcus aureus infection induced septic arthritis by modulating the production of free radicals and endogenous cytokines. Inflamm Res 2013;62:259–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. [47]

    Szekanecz Z, Halloran MM, Volin MV, Woods JM, Strieter RM. Kenneth Haines G3rd, et al. temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum 2000;43:1266–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. [48]

    Medzhitov R. Origin and physiological roles of inflammation. Nature 2008;454:428–35.

    CAS  Article  Google Scholar 

  49. [49]

    Ashley NT, Zachary M, Weil ZM, Nelson RJ. Inflammation: mechanisms, costs, and natural variation. Ann Rev Ecol Evol Syst 2012;43:385–406.

    Article  Google Scholar 

  50. [50]

    Luijten RK, Fritsch-Stork RD, Bijlsma JW, Derksen RH. The use of glucocorticoids in systemic lupus erythematosus: after 60 years still more an art than science. Autoimmun Rev 2013;12:617–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. [51]

    Ruocco E, Wolf R, Ruocco V, Brunetti G, Romano F, Lo Schiavo A. Pemphigus: associations and management guidelines: facts and controversies. Clin Dermatol 2013;31:382–90.

    PubMed  Article  PubMed Central  Google Scholar 

  52. [52]

    Gaujoux-Viala C, Gossec L. When and for how long should glucocorticoids be used in rheumatoid arthritis: international guidelines and recommendations. Ann N Y Acad Sci 2014;1318:32–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. [53]

    Moghadam-Kia S, Werth VP. Prevention and treatment of systemic glucocorticoid side effects. Int J Dermatol 2010;49:239–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. [54]

    Reyes-García G, Medina-Santillán R, Rocha-González HI, Granatos-Soto V. Synergistic interaction between spinal gabapentin and oral B vitamins in a neuropathic pain model. Proc West Pharmacol Soc 2003;46:91–4.

    PubMed  PubMed Central  Google Scholar 

  55. [55]

    Reyes-García G, Caram-Salas NL, Medina-Santillán R, Granatos-Soto V. Oral administration of B vitamins increases the antiallodynic effect of gabapentin in the rat. Proc West Pharmacol Soc 2004;47:76–9.

    PubMed  PubMed Central  Google Scholar 

  56. [56]

    Mixcoatl-Zecuatl T, Quinonez-Bastidas GN, Caram-Salas NL, Ambriz-Tututi M, Araiza-Saldana CI, Rocha-Gonzalez HI, et al. Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats. Methods Find Exp Clin Pharmacol 2008;30:431–41.

    CAS  Article  Google Scholar 

  57. [57]

    Horgan MJ, Palace GP, Everitt JE, Malik AB. TNF-alpha release in endotoxemia contributes to neutrophil-dependent pulmonary edema. Am J Physiol 1993;264:H1161–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. [58]

    Vajja BN, Juluri S, Kumari M, Kole L, Chakrabarti R, Joshi VD. Lipopolysaccharide-induced paw edema model for detection of cytokine modulating anti-inflammatory agents. Int Immunopharmacol 2004;4:901–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. [59]

    Rocha AC, Fernandes ES, Quintão NL, Campos MM, Calixto JB. Relevance of tumour necrosis fator-alpha for the inflammatory and nociceptive responses evoked by carrageenan in the mouse paw. Br J Pharmacol 2006;148:688–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. [60]

    Khong WX, Foo DG, Trasti SL, Tan EL, Alonso S. Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol 2011;85:3067–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. [61]

    Cobianchi L, Fornoni A, Pileggi A, Molano RD, Sanabria NY, Gonzalez-Quintana J, et al. Riboflavin inhibits IL-6 expression and p38 activation in islet cells. Cell Transplant 2008;17:559–66.

    PubMed  Article  PubMed Central  Google Scholar 

  62. [62]

    Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J 2010;429:403–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. [63]

    Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF. Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J 2010;35:750–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. [64]

    Armstrong J, Harbron C, Lea S, Booth G, Cadden P, Wreggett KA, et al. Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2011;338:732–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. [65]

    Yadav UC, Kalariya NM, Srivastava SK, Ramana KV. Protective role of benfotiamine, a fat-soluble vitamin B1 analogue, in lipopolysaccharide-induced cytotoxic signals in murine macrophages. Free Radic Biol Med 2010;48:1423–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. [66]

    Bozic I, Savic D, Laketa D, Bjelobaba I, Milenkovic I, Pekovic S, et al. Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia. PLoS One 2015;10:e0118372.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Márcio M. Coelho.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Menezes, R.R., Godin, A.M., Rodrigues, F.F. et al. Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund’s adjuvant. Pharmacol. Rep 69, 1036–1043 (2017). https://doi.org/10.1016/j.pharep.2017.04.011

Download citation

Keywords

  • Riboflavin
  • Thiamine
  • Corticosteroids
  • Inflammation
  • Cytokines