Abstract
Background: Uric acid (UA) is a strong natural scavenger of reactive oxygen and nitrogen species, with evidence of possible use in the treatment of animal models of multiple sclerosis (MS). Consequently, serum UA has gained much attention as a possible biomarker of MS. We aim to investigate differences in serum UA levels between MS subjects and controls and evaluate possible relationships of UA with MS clinical features.
Methods: We recruited relapsing-remitting and secondary progressive MS subjects and healthy controls and measured their serum UA levels. We excluded subjects presenting concomitant conditions affecting UA levels.
Results: MS subjects (n=362) and controls (n=181) were recruited by propensity score matching (PSM). Statistical analyses were corrected for age, gender, and renal function. MS subjects presented significantly lower serum UA levels than controls (analysis of variance, p=0.014, adjusted r2=0.3036). Linear regression analysis showed a relationship between UA levels and disease duration (p<0.001, adjusted r2=0.3158, coefficient –0.00039), time from diagnosis (p<0.001, adjusted r2=0.3100, coefficient –0.0012), and Expanded Disability Status Scale (EDSS) (p<0.001, adjusted r2=0.3230, coefficient –0.1).
Conclusions: Our findings support the importance of serum UA as a biomarker of MS disability and progression. Further studies with longitudinal design should be specifically designed to evaluate the importance of UA in the different stages of MS and in relation to distinct therapeutic strategies.
References
1. Smith JK, Kapoor R, Felts PA. Demyelination: the role reactive oxygen nitrogen species. Brain Pathol 1991;9:69–92.10.1111/j.1750-3639.1999.tb00212.xSearch in Google Scholar PubMed PubMed Central
2. Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE. Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res Rev 2007;56:322–30.10.1016/j.brainresrev.2007.07.005Search in Google Scholar PubMed
3. Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R, et al. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc Natl Acad Sci USA 1997;94:2528–33.10.1073/pnas.94.6.2528Search in Google Scholar PubMed PubMed Central
4. Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprovski H, et al. Uric acid A peroxynitrite scavenger inhibits CNS inflammation blood-CNS barrier permeability changes and tissue damage in mouse model of multiple sclerosis. FASEB J 2000;14:691–8.10.1096/fasebj.14.5.691Search in Google Scholar PubMed
5. Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, et al. Reaction of uric acid with peroxinitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 2000;376:333–7.10.1006/abbi.2000.1721Search in Google Scholar PubMed
6. Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, Hooper DC. Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci USA 2002;99:16303–8.10.1073/pnas.212645999Search in Google Scholar PubMed PubMed Central
7. Hooper DC, Spitsin S, Kean RB, Champio JM, Dickson GM, Chaudhry I, et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1998;95:675–80.10.1073/pnas.95.2.675Search in Google Scholar PubMed PubMed Central
8. Toncev G, Milicic B, Toncev S, Samardzic G. Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Eur J Neurol 2002;9:221–6.10.1046/j.1468-1331.2002.00384.xSearch in Google Scholar PubMed
9. Dujmovic I, Pekmezovic T, Obrenovic R, Nicolić A, Spasic M, Mostarica Stojkovic M, et al. Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis. Clin Chem Lab Med 2009;47:848–53.10.1515/CCLM.2009.192Search in Google Scholar PubMed
10. Spitsin S, Hooper DC, Mikheeva T, Koprowski H. Uric acid levels in patients with multiple sclerosis: analysis in mono- and dizygotic twins. Mult Scler 2001;7:165–6.10.1177/135245850100700305Search in Google Scholar PubMed
11. Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, et al. Serum uric acid and multiple sclerosis. Neurol Sci 2002; 23:183–8.10.1007/s100720200059Search in Google Scholar PubMed
12. Peng F, Zhang B, Zhong X, Li J, Xu G, Hu X, et al. Serum uric acid levels of patients with multiple sclerosis and other neurological diseases. Mult Scler 2008;14:188–96.10.1177/1352458507082143Search in Google Scholar PubMed
13. Ashtari F, Bahar M, Aghaei M, Zahed A. Serum uric acid level in patients with relapsing-remitting multiple sclerosis. J Clin Neurosci 2013;20:676–8.10.1016/j.jocn.2012.05.054Search in Google Scholar PubMed
14. Drulović J, Dujmović I, Stojsavljević N, Mesaros S, Andjelković S, Miljković D, et al. Uric acid levels in sera from patients with multiple sclerosis. J Neurol 2001;248:121–6.10.1007/s004150170246Search in Google Scholar PubMed
15. Knapp CM, Constantinescu CS, Tan JH, McLean R, Cherryman GR, Gottlob I. Serum uric acid levels in optic neuritis. Mult Scler 2004;10:278–80.10.1191/1352458504ms1042oaSearch in Google Scholar PubMed
16. Liu B, Shen Y, Xiao K, Tang Y, Cen L, Wei J. Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurol Res 2012;34:163–71.10.1179/1743132811Y.0000000074Search in Google Scholar PubMed
17. Guerrero AL, Gutiérrez F, Iglesias F, Martín-Polo J, Merino S, Martín-Serradilla JI, et al. Serum uric acid levels in multiple sclerosis patients inversely correlate with disability. Neurol Sci 2011;32:347–50.10.1007/s10072-011-0488-5Search in Google Scholar PubMed
18. Ljubisavljevic S, Stojanovic I, Vojinovic S, Vojinovic S, Dunjic O, Stojanov D, et al. Association of serum bilirubin and uric acid levels changes during neuroinflammation in patients with initial and relapsed demyelination attacks. Metab Brain Dis 2013;28:629–38.10.1007/s11011-013-9409-zSearch in Google Scholar PubMed
19. Constantinescu CS, Freitag P, Kappos L. Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. Mult Scler 2000;6:378–81.10.1177/135245850000600603Search in Google Scholar PubMed
20. Toncev G, Milicic B, Toncev S, Samardzic G. High-dose methylprednisolone therapy in multiple sclerosis increases serum uric acid levels. Clin Chem Lab Med 2002;40:505–8.10.1515/CCLM.2002.088Search in Google Scholar PubMed
21. Koprowsky H, Spitsin S, Hooper C. Prospects for the treatment of multiple sclerosis by raising serum levels of uric acid, a scavenger of peroxinitrite. Ann Neurol 2001;49:139.10.1002/1531-8249(200101)49:1<139::AID-ANA28>3.0.CO;2-ASearch in Google Scholar
22. Gonsette RE, Sindic C, D’hooghe MB, De Deyn PP, Medaer R, Michotte A, et al. Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing-remitting Multiple Sclerosis (ASIIMS) trial. Mult Scler 2010;16:455–62.10.1177/1352458509360547Search in Google Scholar
23. Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 2001;7:313–9.10.1177/135245850100700507Search in Google Scholar
24. Mostert JP, Ramsaransing GS, Heersema DJ, Heerings M, Wilczak N, De Keyer J. Serum uric acid levels and leukocyte nitric oxide production in multiple sclerosis patients outside relapses. J Neurol Sci 2005;231:41–4.10.1016/j.jns.2004.12.008Search in Google Scholar
25. Ramsaransing GS, Heersema DJ, De Keyser J. Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis. Eur J Neurol 2005;12:514–8.10.1111/j.1468-1331.2005.01009.xSearch in Google Scholar
26. Massa J, O’Reilly E, Munger KL, Delorenze GN, Ascherio A. Serum uric acid and risk of multiple sclerosis. J Neurol 2009;256:1643–8.10.1007/s00415-009-5170-ySearch in Google Scholar
27. Zoccolella S, Tortorella C, Iaffaldano P, Direnzo V, D’Onghia M, Luciannatelli E, et al. Low serum urate levels are associated to female gender in multiple sclerosis patients. PLoS One 2012;7:e40608.10.1371/journal.pone.0040608Search in Google Scholar
28. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, et al. Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 2009;42:1001–6.10.1016/j.clinbiochem.2009.03.020Search in Google Scholar
29. Salemi G, Gueli MC, Vitale F, Battaglieri F, Guglielmini E, Ragonese P, et al. Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. Lipids Health Dis 2010;9:19.10.1186/1476-511X-9-19Search in Google Scholar
30. Tavazzi B, Batocchi AP, Amorini AM, Nociti V, Dúrso S, Longo S, et al. Serum metabolic profile in multiple sclerosis patients. Mult Scler Int 2011;2011:167156.10.1155/2011/167156Search in Google Scholar
31. Koch M, De Keyser J. Uric acid in multiple sclerosis. Neurol Res 2006;28:316–9.10.1179/016164106X98215Search in Google Scholar PubMed
32. Moccia M, Picillo M, Erro R, Vitale C, Longo K, Amboni M, et al. Is serum uric acid related to non-motor symptoms in de-novo Parkinson’s disease patients? Parkinsonism Relat Disord 2014;20:772–5.10.1016/j.parkreldis.2014.03.016Search in Google Scholar PubMed
33. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227–31.10.1002/ana.410130302Search in Google Scholar PubMed
34. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.10.1002/ana.1032Search in Google Scholar PubMed
35. Lublin FD, Reingold SC. 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 1996;46:907–11.10.1212/WNL.46.4.907Search in Google Scholar PubMed
36. Bowman GL, Shannon J, Frei B, Kaye JA, Quinn JF. Uric acid as a CNS antioxidant. J Alzheimers Dis 2010;19:1331–6.10.3233/JAD-2010-1330Search in Google Scholar PubMed PubMed Central
37. Niklasson F, Hetta J, Degrell I. Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid. Ups J Med Sci 1988;93:225–32.10.3109/03009738809178548Search in Google Scholar PubMed
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