Metabolic Brain Disease

, Volume 28, Issue 4, pp 629–638 | Cite as

Association of serum bilirubin and uric acid levels changes during neuroinflammation in patients with initial and relapsed demyelination attacks

  • Srdjan Ljubisavljevic
  • Ivana Stojanovic
  • Slobodan Vojinovic
  • Maja Milojkovic
  • Olivera Dunjic
  • Dragan Stojanov
  • Dusica Pavlovic
Original Paper


In order to examine the endogenous antioxidants values in the earliest phase of demyelination, we have determined bilirubin and uric acid (UA) serum values in the patients with clinically isolated syndrome (CIS) and relapsing remitting multiple sclerosis (RRMS), regarding their clinical disability, measured by Extended Disability Status Scale (EDSS), Magnetic Resonance Imaging (MRI), disease duration, gender and other parameters. The bilirubin and UA levels were lower in CIS and RRMS patients than in control group, whether male or female (p < 0.05). The bilirubin and UA levels were decreased in RRMS compared to CIS patients (p < 0.05). Regarding EDSS, MRI and disease duration, obtained values of bilirubin and UA were higher in both study groups in patients with lower EDSS, lower MRI lesion number and shorter disease duration (p < 0.05). The greatest significance in decreased bilirubin and UA levels was observed in female compared to male patients, in both study groups (p < 0.05). The results suggest negative linear correlation between bilirubin and UA levels and disease duration, EDSS and MRI in CIS (p < 0.01), with the same correlation between bilirubin and UA levels and disease duration in RRMS patients (p < 0.01). There was also significant correlation between bilirubin level and MRI findings and UA levels and EDSS in RRMS patients (p < 0.01). The obtained results point to the importance of endogenous antioxidants in the outbreak and course of neuroinflammation. This could be favorable for the new pathogenetically conditioned neuroinflammatory therapy concepts which do not initially rely only on immunomodulatory, but also on the antioxidative effects.


Bilirubin Uric acid Clinically isolated syndrome Relapsing remitting multiple sclerosis 



This work was supported by the grant from the scientific project number 41018 financed by the Ministry of Education and Science, Republic of Serbia. No conflict of interest exists for any of the authors listed in the article.


  1. Acar AA, Cevik MU, Evliyaoglu O, Uzar E, Tamam Y, Arıkanoglu A, Yucel Y, Varol S, Onder H, Taşdemir N (2012) Evaluation of serum oxidant/antioxidant balance in multiple sclerosis. Acta Neurol Belg 112(3):275–280PubMedCrossRefGoogle Scholar
  2. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, Giovannoni G, Di Pietro V, Polman C, D’Urso S, Vagnozzi R, Uitdehaag B, Lazzarino G (2009) Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 42:1001–1006PubMedCrossRefGoogle Scholar
  3. Bermel RA, Inglese M (2013) Neurodegeneration and inflammation in MS. The eye teaches us about the storm. Neurology 80(1):19–20PubMedCrossRefGoogle Scholar
  4. Chen J, Tu Y, Connolly EC, Ronnett GV (2005) Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP. Curr Neurovasc Res 2:121–131PubMedCrossRefGoogle Scholar
  5. Constantinescu CS, Freitag P, Kappos L (2000) Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. Mult Scler 6(6):378–381PubMedGoogle Scholar
  6. Drulovic J, Dujmovic I, Stojsavljevic N, Mesaros S, Andjelkovic S, Miljkovic D, Peric V, Dragutinovic G, Marinkovic J, Levic Z, Mostarica Stojkovic M (2001) Uric acid levels in sera from patients with multiple sclerosis. J Neurol 248(2):121–126PubMedCrossRefGoogle Scholar
  7. Emerson MR, LeVine SM (2000) Heme oxygenase-1 and NADPH cytochrome P450 reductase expression in experimental allergic encephalomyelitis: an expanded view of the stress response. J Neurochem 75:2555–2562PubMedCrossRefGoogle Scholar
  8. Genc S, Genc K, Kumral A, Baskin H, Ozkan H (2003) Bilirubin is cytotoxic to rat oligodendrocytes in vitro. Brain Res 985:135–141PubMedCrossRefGoogle Scholar
  9. Gilgun-Sherki Y, Melamed E, Offen D (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251(3):261–268PubMedCrossRefGoogle Scholar
  10. Gonsette RE (2008) Oxidative stress and excitotoxicity: a therapeutic issue in multiple sclerosis? Mult Scler 14:22–34PubMedCrossRefGoogle Scholar
  11. Gonsette RE, Sindic C, Dhooghe MB, De Deyn PP, Medaer R, Michotte A, Seeldrayers P, Guillaume D, ASIIMS Study Group (2010) Boosting endogenous neuroprotection in multiple sclerosis: the association of inosine and interferon beta in relapsing-remitting multiple sclerosis (ASIIMS) trial. Mult Scler 16:455–462PubMedCrossRefGoogle Scholar
  12. Guerrero AL, Martın-Polo J, Laherran E, Gutierrez F, Iglesias F, Tejero MA, Rodríguez-Gallego M, Alcázar C (2008) Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment. Eur J Neurol 15:394–397PubMedCrossRefGoogle Scholar
  13. Guerrero L, Gutierrez F, Iglesias F, Martın-Polo J, Merino S, Martın-Serradilla JI, Laherran E, Tejero MA (2011) Serum uric acid levels in multiple sclerosis patients inversely correlate with disability. Neurol Sci 32:347–350PubMedCrossRefGoogle Scholar
  14. Hediger MA (2002) Gateway to a long life? Nature 417:393–395PubMedCrossRefGoogle Scholar
  15. Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, Spitsin SV (2000) Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J 14(5):691–698PubMedGoogle Scholar
  16. Kanabrocki EL, Ryan MD, Hermida RC, Ayala DE, McCormick JB, Dawson S, Lojo L, Hoffman HS, Siegel G, Friedman N, Eladasori B, Parachuri R, Nemchausky BA (2008) Uric acid and renal function in multiple sclerosis. Clin Ter 159:35–40PubMedGoogle Scholar
  17. Kapitulnik J (2004) Bilirubin: an endogenous product of heme degradation with both cytotoxic and cytoprotective properties. Mol Pharmacol 66:773–779PubMedCrossRefGoogle Scholar
  18. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA (2009) Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 61:885–888PubMedCrossRefGoogle Scholar
  19. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedCrossRefGoogle Scholar
  20. Liu Y, Zhu B, Luo L, Li P, Paty DW, Cynader MS (2001) Heme oxygenase-1 plays an important protective role in experimental autoimmune encephalomyelitis. NeuroReport 12:1841–1845PubMedCrossRefGoogle Scholar
  21. Liu Y, Zhu B, Wang X, Luo L, Li P, Paty DW, Cynader MS (2003) Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol 139:27–35PubMedCrossRefGoogle Scholar
  22. Ljubisavljevic S, Stojanovic I, Pavlovic R, Stojnev S, Stevanovic I, Sokolovic D, Pavlovic D (2012) The reduced glutathione and S nitrosothiols levels in acute phase of experimental demyelination—pathophysiological approach and possible clinical relevancy. Neuroscience 219:175–182PubMedCrossRefGoogle Scholar
  23. Ljubisavljevic S, Stojanovic I, Vojinovic S, Stojanov D, Stojanovic S, Cvetkovic T, Savic D, Pavlovic D (2013) The patients with clinically isolated syndrome and relapsing remitting multiples sclerosis show different levels of advanced protein oxidation products and total thiol content in plasma and CSF. Neurochem Int 62(7):988–997Google Scholar
  24. Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey—National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedCrossRefGoogle Scholar
  25. Lundvig DMS, Immenschuh S, Wagener FA (2012) Heme oxygenase, inflammation, and fibrosis: the good, the bad, and the ugly? Front Pharmacol 3:81PubMedCrossRefGoogle Scholar
  26. Maher P, Schubert D (2000) Signaling by reactive oxygen species in the nervous system. Cell Mol Life Sci 57:1287–1305PubMedCrossRefGoogle Scholar
  27. Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem 77:1386–1395PubMedCrossRefGoogle Scholar
  28. Oliveira SR, Kallaur AP, Simao ANC, Morimoto HK, Lopes J, Panis C, Petenucci DL, Silva E, Cecchini R, Kaimen-Maciel DR, Reiche EMV (2012) Oxidative stress in multiple sclerosis patients in clinical remission: association with the expanded disability status scale. J Neurol Sci 321(1–2):49–53PubMedCrossRefGoogle Scholar
  29. Peng F, Zhong X, Deng X, Qiu W, Wu A, Long Y, Hu X, Li Q, Jiang Y, Dai Y (2010) Serum uric acid levels and neuromyelitis optica. J Neurol 257:1021–1026PubMedCrossRefGoogle Scholar
  30. Peng F, Deng X, Yu Y, Chen X, Shen L, Zhong X, Qiu W, Jiang Y, Zhang J, Hu X (2011) Serum bilirubin concentrations and multiple sclerosis. J Clin Neurosci 18:1355–1359PubMedCrossRefGoogle Scholar
  31. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302PubMedCrossRefGoogle Scholar
  32. Ramsaransing GSM, Heersema DJ, De Keyser J (2005) Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs progressive multiple sclerosis. Eur J Neurol 12:514–518PubMedCrossRefGoogle Scholar
  33. Rejdak K, Eikelenboom MJ, Petzold A, Thompson EJ, Stelmasiak Z, Lazeron RHC, Barkhof F, Polman CH, Uitdehaag BMJ, Giovannoni G (2004) CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis. Neurology 63:1439–1445PubMedCrossRefGoogle Scholar
  34. Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D (2006) Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 108(6):527–531PubMedCrossRefGoogle Scholar
  35. Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650PubMedCrossRefGoogle Scholar
  36. Salemi G, Gueli MC, Vitale F, Battaglieri F, Guglielmini E, Ragonese P, Trentacosti A, Massenti MF, Savettieri G, Bono A (2010) Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. Lipids Health Dis 9:19–21PubMedCrossRefGoogle Scholar
  37. Salvatore Orefice N, Ferraro O, Barbato F, Carotenuto A, Lanzillo R, Brescia Morra V, Coppola G, Orefice G (2012) Biochemical parameters alterations in multiple sclerosis: a longitudinal study and review of the literature. Pharmacol Pharm 3:248–253CrossRefGoogle Scholar
  38. Sautin YY, Johnson RJ (2008) Uric acid: the oxidant–antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 27:608–619PubMedCrossRefGoogle Scholar
  39. Scott GS, Hooper DC (2001) The role of uric acid in protection against peroxynitrite-mediated pathology. Med Hypotheses 56(1):95–100PubMedCrossRefGoogle Scholar
  40. Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, Snyder SH (2009) Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. PNAS 106(13):5171–5176PubMedCrossRefGoogle Scholar
  41. Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, Rosati G (2002) Serum uric acid and multiple sclerosis. Neurol Sci 23(4):183–188PubMedCrossRefGoogle Scholar
  42. Toncev G, Milicic B, Toncev S, Samardzic G (2002a) High-dose methylprednisolone therapy in multiple sclerosis increases serum uric acid levels. Clin Chem Lab Med 40(5):505–508PubMedCrossRefGoogle Scholar
  43. Toncev G, Milicic B, Toncev S, Samardzic G (2002b) Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood–brain barrier dysfunction. Eur J Neurol 9(3):221–226PubMedCrossRefGoogle Scholar
  44. Usha SA, Vickneshwaran V, Sanat KS, Thiagaragan G (2011) Bilirubin and uric acid in traumatic brain injury. J Global Pharma Technol 3(11):20–24Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Srdjan Ljubisavljevic
    • 1
    • 2
    • 5
  • Ivana Stojanovic
    • 3
  • Slobodan Vojinovic
    • 1
  • Maja Milojkovic
    • 2
  • Olivera Dunjic
    • 2
  • Dragan Stojanov
    • 4
  • Dusica Pavlovic
    • 3
  1. 1.Clinic of NeurologyClinical Centre NisNisSerbia
  2. 2.Institute for Pathophysiology, Faculty of MedicineUniversity of NisNisSerbia
  3. 3.Institute for Biochemistry, Faculty of MedicineUniversity of NisNisSerbia
  4. 4.Center for RadiologyClinical Centre NisNisSerbia
  5. 5.Faculty of MedicineUniversity of NisNisSerbia

Personalised recommendations