Abstract
Oxidative stress is one of the main mechanisms implicated in the pathophysiology of inflammatory and neurodegenerative diseases of the central nervous system (CNS). Uric acid (UA) is the end product of purine catabolism in humans, and it is the main endogenous antioxidant in blood. Low circulating UA levels have been associated with an increased prevalence and worse clinical course of several neurodegenerative and inflammatory diseases of the CNS, including Parkinson’s disease and multiple sclerosis. Moreover, the exogenous administration of UA exerts robust neuroprotective properties in experimental models of CNS disease, including brain ischemia, spinal cord injury, meningitis, and experimental allergic encephalitis. In experimental brain ischemia, exogenous UA and the thrombolytic agent alteplase exert additive neuroprotective effects when administered in combination. UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with a better outcome and reduced infarct growth at follow-up. A recent phase II trial demonstrated that the combined intravenous administration of UA and alteplase is safe and prevents an early decrease of circulating UA levels in acute ischemic stroke patients. Moreover, UA prevents the increase in the circulating levels of the lipid peroxidation marker malondialdehyde and of active matrix metalloproteinase (MMP) 9, a marker of blood–brain barrier disruption. The moderately sized URICOICTUS phase 2b trial showed that the addition of UA to thrombolytic therapy resulted in a 6 % absolute increase in the rate of excellent outcome at 90 days compared to placebo. The trial also showed that UA administration resulted in a significant increment of excellent outcome in patients with pretreatment hyperglycemia, in females and in patients with moderate strokes. Overall, the encouraging neuroprotective effects of UA therapy in acute ischemic stroke warrants further investigation in adequately powered clinical trials.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004;555:589–606.
Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol. 2012;16:89–95.
Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84.
Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981;78:6858–62.
Santos CX, Anjos EI, Augusto O. Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch Biochem Biophys. 1999;372:285–94.
Gruber J, Tang SY, Jenner AM, Mudway I, Blomberg A, Behndig A, et al. Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: avoiding artifacts and establishing real in vivo concentrations. Antioxid Redox Signal. 2009;11:1767–76.
Hong JM, Bang OY, Chung CS, Joo IS, Gwag BJ, Ovbiagele B. Influence of recanalization on uric acid patterns in acute ischemic stroke. Cerebrovasc Dis. 2010;29:431–9.
Ozkan Y, Yardim-Akaydin S, Imren E, Torun M, Simsek B. Increased plasma homocysteine and allantoin levels in coronary artery disease: possible link between homocysteine and uric acid oxidation. Acta Cardiol. 2006;61:432–9.
Kand’ar R, Zakova P. Allantoin as a marker of oxidative stress in human erythrocytes. Clin Chem Lab Med. 2008;46:1270–4.
Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med. 1993;14:615–31.
Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, et al. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000;376:333–7.
Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. Biochem Pharmacol. 2005;70:343–54.
Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des. 2005;11:4145–51.
Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, Morens DM. Observations on serum uric acid levels and the risk of idiopathic Parkinson’s disease. Am J Epidemiol. 1996;144:480–4.
Drulovic J, Dujmovic I, Stojsavljevic N, Mesaros S, Andjelkovic S, Miljkovic D, et al. Uric acid levels in sera from patients with multiple sclerosis. J Neurol. 2001;248:121–6.
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.
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.
Ashtari F, Bahar M, Aghaei M, Zahed A. Serum uric acid level in patients with relapsing-remitting multiple sclerosis. J Clin Neurosci. 2013;20(5):676–8.
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.
Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging. 2003;24:915–9.
Keizman D, Ish-Shalom M, Berliner S, Maimon N, Vered Y, Artamonov I, et al. Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress? J Neurol Sci. 2009;285:95–9.
Paganoni S, Zhang M, Quiroz Zarate A, Jaffa M, Yu H, Cudkowicz ME, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol. 2012;259:1923–8.
Scott GS, Hooper DC. The role of uric acid in protection against peroxynitrite-mediated pathology. Med Hypotheses. 2001;56:95–100.
Chamorro A, Planas AM, Muner DS, Deulofeu R. Uric acid administration for neuroprotection in patients with acute brain ischemia. Med Hypotheses. 2004;62:173–6.
Muraoka S, Miura T. Inhibition by uric acid of free radicals that damage biological molecules. Pharmacol Toxicol. 2003;93:284–9.
Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003;41:1287–93.
Kang DH, Han L, Ouyang X, Kahn AM, Kanellis J, Li P, et al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol. 2005;25:425–33.
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67:1739–42.
Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16:3553–62.
Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007;293:C584–96.
Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002;13:2888–97.
Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995;141:637–44.
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA. 2000;283:2404–10.
Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004;164:1546–51.
Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke. 2006;37:1503–7.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.
Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids. 2008;27:608–19.
Proctor PH. Uric acid: neuroprotective or neurotoxic? Stroke. 2008;39:e88. author reply e89.
Dringen R. Metabolism and functions of glutathione in brain. Prog Neurobiol. 2000;62:649–71.
Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.
Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315–424.
Hensley K, Maidt ML, Yu Z, Sang H, Markesbery WR, Floyd RA. Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J Neurosci. 1998;18:8126–32.
Whiteman M, Ketsawatsakul U, Halliwell B. A reassessment of the peroxynitrite scavenging activity of uric acid. Ann N Y Acad Sci. 2002;962:242–59.
Aoyama K, Matsumura N, Watabe M, Wang F, Kikuchi-Utsumi K, Nakaki T. Caffeine and uric acid mediate glutathione synthesis for neuroprotection. Neuroscience. 2011;181:206–15.
Du Y, Chen CP, Tseng CY, Eisenberg Y, Firestein BL. Astroglia-mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity. Glia. 2007;55:463–72.
Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. 1998;53:613–25.
Romanos E, Planas AM, Amaro S, Chamorro A. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007;27:14–20.
Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, et al. 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. 2000;14:691–8.
Spitsin SV, Scott GS, Kean RB, Mikheeva T, Hooper DC. Protection of myelin basic protein immunized mice from free-radical mediated inflammatory cell invasion of the central nervous system by the natural peroxynitrite scavenger uric acid. Neurosci Lett. 2000;292:137–41.
Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC. The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol. 2000;165:6511–8.
Scott GS, Cuzzocrea S, Genovese T, Koprowski H, Hooper DC. Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci U S A. 2005;102:3483–8.
Lipton P. Ischemic cell death in neurons. Physiol Rev. 1999;79:1431–568.
Fisher M, Bastan B. Identifying and utilizing the ischemic penumbra. Neurology. 2012;79(13 Suppl 1):S79–85.
Fukuyama N, Takizawa S, Ishida H, Hoshiai K, Shinohara Y, Nakazawa H. Peroxynitrite formation in focal cerebral ischemia-reperfusion in rats occurs predominantly in the peri-infarct region. J Cereb Blood Flow Metab. 1998;18:123–955.
Morimoto T, Globus MY, Busto R, Martinez E, Ginsberg MD. Simultaneous measurement of salicylate hydroxylation and glutamate release in the penumbral cortex following transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 1996;16:92–9.
Berkhemer OA, Fransen PS, Beumer D, van den Berg D, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JM, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–30.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–18.
Saver JL, Goyal M, Bonafe A, Diener HC, Levy E, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–95.
Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–306.
Schaller B, Graf R. Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab. 2004;24:351–71.
Fabian RH, DeWitt DS, Kent TA. In vivo detection of superoxide anion production by the brain using a cytochrome c electrode. J Cereb Blood Flow Metab. 1995;15:242–7.
Crack PJ, Taylor JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med. 2005;38:1433–44.
Pfefferkorn T, Rosenberg GA. Closure of the blood–brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003;34:2025–30.
Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood–brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1393–400.
Amaro S, Chamorro A. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke. 2011;42:1495–9.
Weir CJ, Muir SW, Walters MR, Lees KR. Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke. 2003;34:1951–6.
Karagiannis A, Mikhailidis DP, Tziomalos K, Sileli M, Savvatianos S, Kakafika A, et al. Serum uric acid as an independent predictor of early death after acute stroke. Circ J. 2007;71:1120–7.
Chiquete E, Ruiz-Sandoval JL, Murillo-Bonilla LM, Arauz A, Orozco-Valera DR, Ochoa-Guzman A, et al. Serum uric acid and outcome after acute ischemic stroke: PREMIER study. Cerebrovasc Dis. 2013;35:168–74.
Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002;33:1048–52.
Amaro S, Urra X, Gomez-Choco M, Obach V, Cervera A, Vargas M, et al. Uric acid levels are relevant in patients with stroke treated with thrombolysis. Stroke. 2011;42:S28–32.
Logallo N, Naess H, Idicula TT, Brogger J, Waje-Andreassen U, Thomassen L. Serum uric acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study. BMC Neurol. 2011;11:114.
Dawson J, Lees KR, Weir CJ, Quinn T, Ali M, Hennerici MG, et al. Baseline serum urate and 90-day functional outcomes following acute ischemic stroke. Cerebrovasc Dis. 2009;28:202–3.
Miedema I, Uyttenboogaart M, Koch M, Kremer B, de Keyser J, Luijckx GJ. Lack of association between serum uric acid levels and outcome in acute ischemic stroke. J Neurol Sci. 2012;319:51–5.
Seet RC, Kasiman K, Gruber J, Tang SY, Wong MC, Chang HM, et al. Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study. Atherosclerosis. 2010;209:215–9.
Wang Z, Lin Y, Liu Y, Chen Y, Wang B, Li C, et al. Serum uric acid levels and outcomes after acute ischemic stroke. [published online ahead of print March 7, 2015] Mol Neurobiol 2015. http://www.ncbi.nlm.nih.gov/pubmed/25744569. Accessed April 27 2015. This systematic meta-analysis includes 8131 patients from 10 different studies. The results support that serum uric acid concentration at onset is a useful biomarker of outcome after stroke and that high uric acid levels show a protective effect on neurological outcome after acute ischemic stroke.
Amaro S, Planas AM, Chamorro A. Uric acid administration in patients with acute stroke: a novel approach to neuroprotection. Expert Rev Neurother. 2008;8:259–70.
Gariballa SE, Hutchin TP, Sinclair AJ. Antioxidant capacity after acute ischaemic stroke. QJM. 2002;95:685–90.
Amaro S, Soy D, Obach V, Cervera A, Planas AM, Chamorro A. A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke. Stroke. 2007;38:2173–5.
Brouns R, Wauters A, Van De Vijver G, De Surgeloose D, Sheorajpanday R, De Deyn PP. Decrease in uric acid in acute ischemic stroke correlates with stroke severity, evolution and outcome. Clin Chem Lab Med. 2010;48:383–90.
Ma YH, Su N, Chao XD, Zhang YQ, Zhang L, Han F, et al. Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress. Neurochem Int. 2012;60:475–83. Ma YH et al. conducted an experimental study in mice subjected to cerebral ischemia. The results showed that thioredoxin-1 and uric acid diminish peroxinitrite and superoxide anion formation resulting in an antioxidative/antinitrative effect and a reduction of apoptotic cell death and infarct size.
Haberman F, Tang SC, Arumugam TV, Hyun DH, Yu QS, Cutler RG, et al. Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice. Neuromol Med. 2007;9:315–23.
Onetti Y, Dantas AP, Pérez B, Cugota R, Chamorro A, Planas AM, et al. Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: a target of uric acid treatment. Am J Physiol Heart Circ Physiol. 2015;308(8):H862–74. In this experimental study in hyperemic rats, Onetti Y et al. showed that UA administration reduces infarct volume and improves clinical outcome after stroke. The main mechanisms suggested for this neuroprotective effect are the inhibition of middle cerebral artery remodeling. The effect on brain vessels observed in this study identifies a novel potential therapeutic target of uric acid after ischemic stroke.
Recommendations for clinical trial evaluation of acute stroke therapies. Stroke 2001; 32:1598–1606.
Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood–brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:32.
Amaro S, Obach V, Cervera A, Urra X, Gomez-Choco M, Planas AM, et al. Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study. J Neurol. 2009;256:651–6.
Chamorro A, Amaro S, Castellanos M, Segura T, Arenillas J, Martí-Fábregas J, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomized, double-blind, phase 2b/3 trial. Lancet Neurol. 2014;13:453–60. This randomized placebo-controlled clinical trial included 420 patients from 10 comprehensive stroke centers. Uric acid administration showed no safety concerns and increased the rate of excellent outcome in treated patients compared to the placebo group.
Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycemia. Lancet. 2009;373:1798–807.
Robbins NM, Swanson RA. Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism. Stroke. 2014;45:1881–6. This is an extensive summary of the mechanisms by which hyperglycemia can exacerbate brain injury in the acute stroke setting based on clinical observations and the results of the most relevant clinical trials addressing this topic.
Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, et al. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol. 2008;64:654–63.
Amaro S, Llull L, Renú A, Laredo C, Perez B, Vila E, et al. Uric acid improves glucose-driven oxidative stress in human ischemic stroke. Ann Neurol. 2015;77:775–83. This re-analysis of the URICO-ICTUS data evaluated the role of hyperglycemia on the neuroprotective effect of uric acid in acute ischemic stroke patients treated with alteplase. The results showed that administration of UA is more effective in hyperglycemic patients and patients with early arterial recanalization.
Llull L, Laredo C, Renú A, Perez B, Vila E, Obach V, et al. Uric acid therapy improves clinical outcome in women with acute ischemic stroke. Stroke. 2015. In press. This re-analysis of the URICO-ICTUS data evaluated the role of sex on the neuroprotective effect of uric acid administration together with alteplase in acute ischemic stroke patients. The results showed that UA is more effective than placebo in improving clinical outcome and limiting infarct growth in women than in men.
Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7(10):915–26.
Campbell BC, Davis SM, Donnan GA. Uric acid for stroke: glimmer of hope or false dawn? Lancet Neurol. 2014;13(5):440–1.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Laura Llull and Sergio Amaro declare that they have no conflict of interest. Ángel Chamorro is inventor of the patent “Pharmaceutical composition for neuroprotective treatment in patients with ictus comprising citicoline and uric acid” and whose proprietor is Hospital Clinic in Provincial of Barcelona, Spain.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Stroke
Rights and permissions
About this article
Cite this article
Llull, L., Amaro, S. & Chamorro, Á. Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke. Curr Neurol Neurosci Rep 16, 4 (2016). https://doi.org/10.1007/s11910-015-0604-7
Published:
DOI: https://doi.org/10.1007/s11910-015-0604-7