Background Urate is a natural antioxidant and may prevent CNS tissue damage and the clinical manifestations of experimental autoimmune encephalitis. Results from clinical studies are conflicting and the contribution of urate to the pathogenesis of Multiple Sclerosis (MS) remains uncertain. Objective To evaluate serum urate levels in MS patients and their relationships with clinical, demographic and MRI variables. Methods Levels of non-fasting serum uric acid and creatinine were determined by an automated enzymatic assay and glomerular filtration rate was assessed in 245 MS patients, in 252 age/sex-matched neurological controls (NC) and in 59 Healthy controls (HC). Results Median serum urate levels did not differ between MS patients (3.8 mg/dL), HC (4.0 mg/dl) and NC (4.0 mg/dL). Serum urate levels were lower in females than in males in all groups (p = <0.0001). In female-MS, serum urate levels (3.2 mg/dL) were lower compared to those in female HC (3.8; p = 0.01) and NC (3.5 mg/dL; p = 0.02), whereas in male-MS they(4.8 mg/dL) did not differ from those in male HC (4.5 mg/dl) and NC (4.8 mg/dL). Urate concentrations trended to be lower in Clinically isolated syndromes suggestive of MS (3.7 mg/dL) and in relapsing MS (3.7 mg/dL), compared to patients with progressive MS (4.4 mg/dL; p = 0.06), and in patients with an annual relapse rate (ARR) >2 (3.3 mg/dL) than in those with an ARR ≤2: 3.9 mg/dL; p = 0.05). Significant lower serum urate levels were found in females than in males in all clinical MS subtypes (p<0.01), separately evaluated. Female sex (beta: ？0.53; p<0.00001) was the most significant determinant of serum urate concentrations in MS patients on multivariate regression analysis. Conclusions Our findings suggest that low urate levels could be of significance in predominantly inflammatory phases of MS even at the early stage and mainly in females.
References
[1]
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple Sclerosis. N Engl J Med 343: 938–952.
[2]
Oda M, Satta Y, Takenaka O, Takahata N (2002) Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol19: 640–653.
[3]
Ames BN, Cathcart R, Schwiers E, Hochstein P (1988) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA. 78: 6858–6862.
[4]
Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58: 495–505.
[5]
Kutzing MK, Firestein BL (2008) Altered uric acid levels and disease states. J Pharmacol Exp Ther 324: 1–7.
[6]
Moore GR (2010) Current concepts in the neuropathology and pathogenesis of multiple sclerosis. Can J Neurol Sci 37 Suppl 2S5–15.
[7]
van der Veen RC, Roberts LJ (1999) Contrasting roles for nitric oxide and peroxynitritein the peroxidation of myelin lipids. J Neuroimmunol 95: 1–7.
[8]
Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM, et al. (1998) Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 95: 675–680.
[9]
Drulovi？ J, Dujmovi？ I, Stojsavljevi？ N, Mesaros S, Andjelkovi？ S, et al. (2001) Uric acid levels in sera from patients with multiple sclerosis. J Neurol 248: 121–126.
[10]
Spitsin S, Hooper DC, Mikheeva T, Koprowski H (2001) Uric acid levels in patients with multiple sclerosis: analysis in mono- and dizygotic twins. Mult Scler 7: 165–166.
[11]
Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, et al. (2002) Serum uric acid and multiple sclerosis. Neurol Sci 23: 183–188.
[12]
Dujmovic I, Pekmezovic T, Obrenovic R, Nikoli？ A, Spasic M, et al. (2009) Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis. ClinChem Lab Med 47: 848–853.
[13]
Peng F, Zhang B, Zhong X, Li J, Xu G, et al. (2008) Serum uric acid levels of patients with multiple sclerosis and other neurological diseases. Mult Scler 14: 188–196.
[14]
Zamani A, Rezaei A, Khaeir F, Hooper DC (2008) Serum and cerebrospinal fluid uric acid levels in multiple sclerosis patients. Clin Neurol Neurosurg 110: 642–643.
[15]
Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, et al. (2006) Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 108: 527–531.
[16]
Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, et al. (2009) Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 42: 1001–1006.
[17]
Tavazzi B, Batocchi AP, Amorini AM, Nociti V, D’Urso S, et al. (2011) Serum metabolic profile in multiple sclerosis patients. Mult Scler Int 2011: 167156.
[18]
Salemi G, Gueli MC, Vitale F, Battaglieri F, Guglielmini E, et al. (2010) Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. Lipids Health Dis 9: 19.
[19]
Toncev G, Milicic B, Toncev S, Samardzic G (2002) Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Eur J Neurol 9: 221–226.
[20]
Fuhua P, Xuhui D, Zhiyang Z, Ying J, Yu Y, et al. (2012) Antioxidant status of bilirubin and uric acid in patients with myasthenia gravis. Neuroimmunomodulation 19: 43–49.
[21]
Karg E, Klivényi P, Németh I, Bencsik K, Pintér S, et al. (1999) Nonenzymatic antioxidants of blood in multiple sclerosis. J Neurol 246: 533–539.
[22]
Becker BF, Kastenbauer S, K？del U, Kiesl D, Pfister HW (2004) Urate oxidation in CSF and blood of patients with inflammatory disorders of the nervous system. Nucleosides Nucleotides Nucleic Acids 23: 1201–1204.
[23]
Miller E, Walczak A, Saluk J, Ponczek MB, Majsterek I (2012) Oxidative modification of patient’s plasma proteins and its role in pathogenesis of multiple sclerosis. ClinBiochem 45: 26–30.
[24]
Mostert JP, Ramsaransing GS, Heersema DJ, Heerings M, Wilczak N, et al. (2005) Serum uric acid levels and leukocyte nitric oxide production in multiple sclerosis patients outside relapses. J Neurol Sci 231: 41–44.
[25]
Ramsaransing GS, 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: 514–518.
[26]
Massa J, O’Reilly E, Munger KL, Delorenze GN, Ascherio A (2009) Serum uric acid and risk of multiple sclerosis. J Neurol 256: 1643–1648.
[27]
Kanabrocki EL, Ryan MD, Hermida RC, Ayala DE, McCormick JB, et al. (2008) Uric acid and renal function in multiple sclerosis. Clin Ter 159: 35–40.
[28]
Liu B, Shen Y, Xiao K, Tang Y, Cen L, et al. (2012) Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurol Res 34: 163–171.
[29]
Gonsette RE, Sindic C, D’hooghe MB, De Deyn PP, Medaer R, et al. (2010) Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial. Mult Scler 16: 455–462.
[30]
Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, et al. (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58: 840–846.
[31]
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, et al. (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69: 292–302.
[32]
Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM (2006) Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 37: 1503–1507.
[33]
Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, et al. (2007) Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem 53: 766–772.
[34]
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33: 1444–1452.
[35]
Greer JM, McCombe PA (2011) Role of gender in multiple sclerosis: Clinical effects and potential molecular mechanisms. J Neuroimmunology 234: 7–18.
[36]
Guerrero AL, Martín-Polo J, Laherrán E, Gutiérrez F, Iglesias F, et al. (2008) Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment. Eur J Neurol 15: 394–397.
[37]
Gasteyger C, Suter M, Calmes JM, Gaillard RC, Giusti V (2006) Changes in body composition, metabolic profile and nutritional status 24 months after gastric banding. Obes Surg 16: 243–250.
