{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:03:19Z","timestamp":1784264599339,"version":"3.55.0"},"reference-count":103,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer\u2019s disease, amyotrophic lateral sclerosis, Huntington\u2019s disease, Parkinson\u2019s disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization.<\/jats:p>","DOI":"10.3390\/antiox14040483","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T04:16:21Z","timestamp":1744863381000},"page":"483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Xanthine Oxidoreductase: A Double-Edged Sword in Neurological Diseases"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-2237","authenticated-orcid":false,"given":"Massimo","family":"Bortolotti","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences\u2014DIMEC, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8051-4981","authenticated-orcid":false,"given":"Letizia","family":"Polito","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences\u2014DIMEC, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6048-0454","authenticated-orcid":false,"given":"Maria Giulia","family":"Battelli","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences\u2014DIMEC, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7497-4586","authenticated-orcid":false,"given":"Andrea","family":"Bolognesi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences\u2014DIMEC, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","unstructured":"GBD 2016 Neurology Collaborators (2019). Global, regional, and national burden of neurological disorders, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 18, 459\u2013480."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.expneurol.2017.06.017","article-title":"Targeting urate to reduce oxidative stress in Parkinson disease","volume":"298","author":"Crotty","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7191080","DOI":"10.1155\/2020\/7191080","article-title":"Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development","volume":"2020","author":"Pegoretti","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3233\/JAD-161088","article-title":"Oxidative Stress, Synaptic Dysfunction, and Alzheimer\u2019s Disease","volume":"57","author":"Trushina","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jns.2009.06.002","article-title":"Low uric acid levels in serum of patients with ALS: Further evidence for oxidative stress?","volume":"285","author":"Keizman","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3233\/JHD-160205","article-title":"Oxidative Stress and Huntington\u2019s Disease: The Good, the Bad, and the Ugly","volume":"5","author":"Kumar","year":"2016","journal-title":"J. Huntingtons Dis."},{"key":"ref_7","first-page":"2360872","article-title":"Oxidative Stress in Parkinson\u2019s Disease: Potential Benefits of Antioxidant Supplementation","volume":"2020","author":"Varela","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8418820","DOI":"10.1155\/2022\/8418820","article-title":"The Role of Oxidative Stress in Acute Ischemic Stroke-Related Thrombosis","volume":"2022","author":"Li","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12964-024-01965-4","article-title":"Targeting uric acid: A promising intervention against oxidative stress and neuroinflammation in neurodegenerative diseases","volume":"23","author":"Xu","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3527579","DOI":"10.1155\/2016\/3527579","article-title":"Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects","volume":"2016","author":"Battelli","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bortolotti, M., Polito, L., Battelli, M.G., and Bolognesi, A. (2021). Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol., 41.","DOI":"10.1016\/j.redox.2021.101882"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41573-022-00390-x","article-title":"Function and therapeutic value of astrocytes in neurological diseases","volume":"21","author":"Lee","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1111\/febs.13277","article-title":"The C-terminal peptide plays a role in the formation of an intermediate form during the transition between xanthine dehydrogenase and xanthine oxidase","volume":"282","author":"Nishino","year":"2015","journal-title":"FEBS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.semnephrol.2011.08.002","article-title":"Uric acid: A danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: Evolutionary considerations","volume":"31","author":"Johnson","year":"2011","journal-title":"Semin. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.2174\/1568026615666150610143234","article-title":"The Role of Uric Acid and Methyl Derivatives in the Prevention of Age-Related Neurodegenerative Disorders","volume":"15","author":"Cutler","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152358","DOI":"10.1016\/j.semarthrit.2023.152358","article-title":"Moving urate-lowering therapy in gout beyond guideline recommendations","volume":"65","author":"Stamp","year":"2024","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gherghina, M.E., Peride, I., Tiglis, M., Neagu, T.P., Niculae, A., and Checherita, I.A. (2022). Uric Acid and Oxidative Stress-Relationship with Cardiovascular, Metabolic, and Renal Impairment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063188"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yu, W., and Cheng, J.D. (2020). Uric acid and cardiovascular disease: An update from molecular mechanism to clinical perspective. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.582680"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nakayama, A., Kurajoh, M., Toyoda, Y., Takada, T., Ichida, K., and Matsuo, H. (2023). Dysuricemia. Biomedicines, 11.","DOI":"10.3390\/biomedicines11123169"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Scioli, M.G., Storti, G., D\u2019Amico, F., Rodr\u00edguez Guzm\u00e1n, R., Centofanti, F., Doldo, E., C\u00e9spedes Miranda, E.M., and Orlandi, A. (2020). Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061995"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, F., Yuan, Q., Chen, F., Pang, J., Pan, C., Xu, F., and Chen, Y. (2021). Fundamental Mechanisms of the Cell Death Caused by Nitrosative Stress. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.742483"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/j.bbadis.2014.05.022","article-title":"Pathophysiology of circulating xanthine oxidoreductase: New emerging roles for a multi-tasking enzyme","volume":"1842","author":"Battelli","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/jgh.12072","article-title":"Sterile inflammation in hepatic ischemia\/reperfusion injury: Present concepts and potential therapeutics","volume":"28","author":"Reiniers","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Reichert, C.O., de Freitas, F.A., Sampaio-Silva, J., Rokita-Rosa, L., Barros, P.L., Levy, D., and Bydlowski, S.P. (2020). Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228765"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13024-023-00691-8","article-title":"Microglial ferroptotic stress causes non-cell autonomous neuronal death","volume":"19","author":"Liddell","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Battelli, M.G., Bortolotti, M., Bolognesi, A., and Polito, L. (2020). Pro-Aging Effects of Xanthine Oxidoreductase Products. Antioxidants, 9.","DOI":"10.3390\/antiox9090839"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42808","DOI":"10.18632\/oncotarget.17057","article-title":"Mechanism of oxidative stress p38MAPK-SGK1 signaling axis in experimental autoimmune encephalomyelitis (EAE)","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"D\u0105browska-Bouta, B., Stru\u017cy\u0144ska, L., Sidoryk-W\u0119grzynowicz, M., and Sulkowski, G. (2021). Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111330"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s11064-016-2094-7","article-title":"Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit","volume":"42","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Trifunovic, S., Stevanovic, I., Milosevic, A., Ristic, N., Janjic, M., Bjelobaba, I., Savic, D., Bozic, I., Jakovljevic, M., and Tesovic, K. (2021). The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.649485"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/npr2.12360","article-title":"Effects of N-acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis","volume":"43","author":"Hosseini","year":"2023","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s10072-011-0488-5","article-title":"Serum uric acid levels in multiple sclerosis patients inversely correlate with disability","volume":"32","author":"Guerrero","year":"2011","journal-title":"Neurol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1179\/1743132811Y.0000000074","article-title":"Serum uric acid levels in patients with multiple sclerosis: A meta-analysis","volume":"34","author":"Liu","year":"2012","journal-title":"Neurol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00415-015-7666-y","article-title":"Uric acid in relapsing-remitting multiple sclerosis: A 2-year longitudinal study","volume":"262","author":"Moccia","year":"2015","journal-title":"J. Neurol."},{"key":"ref_35","unstructured":"GBD 2016 Dementia Collaborators (2019). Global, regional, and national burden of Alzheimer\u2019s disease and other dementias, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 18, 88\u2013106."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s42255-023-00756-4","article-title":"Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration","volume":"5","author":"Mi","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/glia.23741","article-title":"NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer\u2019s disease astrocytes","volume":"68","author":"Oksanen","year":"2020","journal-title":"Glia"},{"key":"ref_38","first-page":"346783","article-title":"Ceramides in Alzheimer\u2019s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and A\u03b2 Accumulation","volume":"2015","author":"Hof","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.1007\/s12035-023-03818-6","article-title":"Uric Acid Mitigates Cognitive Deficits via TFEB-Mediated Microglial Autophagy in Mice Models of Alzheimer\u2019s Disease","volume":"61","author":"Xiao","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.ajcnut.2023.01.002","article-title":"Could Alzheimer\u2019s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?","volume":"117","author":"Johnson","year":"2023","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/annrheumdis-2014-206917","article-title":"Gout and the risk of Alzheimer\u2019s disease: A population-based, BMI-matched cohort study","volume":"75","author":"Lu","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1152\/physrev.00030.2022","article-title":"Oxidative damage in neurodegeneration: Roles in the pathogenesis and progression of Alzheimer disease","volume":"104","author":"Perluigi","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ibneur.2023.11.003","article-title":"Current biomarkers and treatment strategies in Alzheimer disease: An overview and future perspectives","volume":"16","author":"Bhole","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1007\/s00415-012-6440-7","article-title":"Uric acid levels predict survival in men with amyotrophic lateral sclerosis","volume":"259","author":"Paganoni","year":"2012","journal-title":"J. Neurol."},{"key":"ref_45","first-page":"140","article-title":"Clinical outcomes and serum uric acid levels in elderly patients with amyotrophic lateral sclerosis aged \u226570 years","volume":"2","author":"Kataoka","year":"2013","journal-title":"Am. J. Neurodegener. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xu, L.Q., Hu, W., Guo, Q.F., Xu, G.R., Wang, N., and Zhang, Q.J. (2021). Serum Uric Acid Levels Predict Mortality Risk in Male Amyotrophic Lateral Sclerosis Patients. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.602663"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1080\/21678421.2016.1214733","article-title":"Serum urate at trial entry and ALS progression in EMPOWER","volume":"18","author":"Liu","year":"2017","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhang, F., Zhang, Q., Ke, Y., Hao, J., Lu, L., Lu, N., and Chen, X. (2018). Serum uric acid levels in patients with amyotrophic lateral sclerosis: A meta-analysis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19609-2"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s00415-023-12056-8","article-title":"High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis","volume":"271","author":"Iazzolino","year":"2024","journal-title":"J. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/mds.22907","article-title":"The relationship between uric acid levels and Huntington\u2019s disease progression","volume":"25","author":"Auinger","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1021\/acs.jproteome.6b00049","article-title":"Novel Metabolite Biomarkers of Huntington\u2019s Disease as Detected by High-Resolution Mass Spectrometry","volume":"15","author":"Graham","year":"2016","journal-title":"J. Proteome Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Corey-Bloom, J., Haque, A., Aboufadel, S., Snell, C., Fischer, R.S., Granger, S.W., Granger, D.A., and Thomas, E.A. (2020). Uric Acid as a Potential Peripheral Biomarker for Disease Features in Huntington\u2019s Patients. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00073"},{"key":"ref_53","unstructured":"GBD 2016 Parkinson\u2019s Disease Collaborators (2018). Global, regional, and national burden of Parkinson\u2019s disease, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 17, 939\u2013953. Erratum in: Lancet Neurol. 2021, 20, e7."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","article-title":"Parkinson\u2019s Progression Markers Initiative. Assessment of heterogeneity among participants in the Parkinson\u2019s Progression Markers Initiative cohort using \u03b1-synuclein seed amplification: A cross-sectional study","volume":"22","author":"Siderowf","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41392-023-01353-3","article-title":"Signaling pathways in Parkinson\u2019s disease: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Yong","year":"2023","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e22723","DOI":"10.1096\/fj.202201436R","article-title":"Xanthine oxidoreductase mediates genotoxic drug-induced autophagy and apoptosis resistance by uric acid accumulation and TGF-\u03b2-activated kinase 1 (TAK1) activation","volume":"37","author":"Wang","year":"2023","journal-title":"FASEB J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.expneurol.2017.08.007","article-title":"Urate promotes SNCA\/\u03b1-synuclein clearance via regulating mTOR-dependent macroautophagy","volume":"297","author":"Sheng","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Shin, Y.J., Kim, Y.J., Lee, J.E., Kim, Y.S., Lee, J.W., Kim, H., Shin, J.Y., and Lee, P.H. (2023). Uric acid regulates \u03b1-synuclein transmission in Parkinsonian models. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1117491"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/toxsci\/kft112","article-title":"Glutathione deficiency in Gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration","volume":"134","author":"Liang","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Chang, K.H., and Chen, C.M. (2020). The Role of Oxidative Stress in Parkinson\u2019s Disease. Antioxidants, 9.","DOI":"10.3390\/antiox9070597"},{"key":"ref_61","first-page":"505","article-title":"Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson\u2019s Disease in the Harvard Biomarkers Study","volume":"10","author":"Bakshi","year":"2020","journal-title":"J. Park. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.parkreldis.2020.12.020","article-title":"Serum uric acid level as a putative biomarker in Parkinson\u2019s disease patients carrying GBA1 mutations: 2-Year data from the PPMI study","volume":"84","author":"Koros","year":"2021","journal-title":"Park. Relat. Disord."},{"key":"ref_63","first-page":"1571","article-title":"Does Serum Urate Change as Parkinson\u2019s Disease Progresses?","volume":"10","author":"Hasimoglu","year":"2020","journal-title":"J. Park. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1007\/s10072-021-05558-8","article-title":"Low serum uric acid levels are associated with the nonmotor symptoms and brain gray matter volume in Parkinson\u2019s disease","volume":"43","author":"Shi","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Gra\u017cy\u0144ska, A., Adamczewska, K., Antoniuk, S., Bie\u0144, M., To\u015b, M., Kufel, J., Urba\u015b, W., and Siuda, J. (2021). The Influence of Serum Uric Acid Level on Non-Motor Symptoms Occurrence and Severity in Patients with Idiopathic Parkinson\u2019s Disease and Atypical Parkinsonisms-A Systematic Review. Medicina, 57.","DOI":"10.3390\/medicina57090972"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"811","DOI":"10.3233\/JPD-230007","article-title":"Serum Uric Acid as a Putative Biomarker in Prodromal Parkinson\u2019s Disease: Longitudinal Data from the PPMI Study","volume":"13","author":"Koros","year":"2023","journal-title":"J. Parkinsons Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13024-025-00797-1","article-title":"Emerging targets of \u03b1-synuclein spreading in \u03b1-synucleinopathies: A review of mechanistic pathways and interventions","volume":"20","author":"Kuo","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Starr, L.A., McKay, L.E., Peter, K.N., Seyfarth, L.M., Berkowitz, L.A., Caldwell, K.A., and Caldwell, G.A. (2023). Attenuation of Dopaminergic Neurodegeneration in a C. elegans Parkinson\u2019s Model through Regulation of Xanthine Dehydrogenase (XDH-1) Expression by the RNA Editase, ADR-2. J. Dev. Biol., 11.","DOI":"10.20944\/preprints202303.0230.v1"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Thies, J.L., Willicott, K., Craig, M.L., Greene, M.R., DuGay, C.N., Caldwell, G.A., and Caldwell, K.A. (2023). Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in C. elegans. Cells, 12.","DOI":"10.3390\/cells12081170"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Haryuni, R.D., Nukui, T., Piao, J.L., Shirakura, T., Matsui, C., Sugimoto, T., Baba, K., Nakane, S., and Nakatsuji, Y. (2024). Elevated Serum Xanthine Oxidase and Its Correlation with Antioxidant Status in Patients with Parkinson\u2019s Disease. Biomolecules, 14.","DOI":"10.3390\/biom14040490"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Song, Y., Racette, B.A., Camacho-Soto, A., and Searles Nielsen, S. (2023). Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0285011"},{"key":"ref_73","unstructured":"GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795\u2013820."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1161\/CIRCRESAHA.116.309326","article-title":"Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis","volume":"120","author":"Xia","year":"2017","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1016\/j.bbadis.2018.05.003","article-title":"The role of xanthine oxidoreductase and uric acid in metabolic syndrome","volume":"1864","author":"Battelli","year":"2018","journal-title":"Biochim. Biophys. Acta\u2014Mol. Basis Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.atherosclerosis.2014.10.006","article-title":"Xanthine oxidoreductase in atherosclerosis pathogenesis: Not only oxidative stress","volume":"237","author":"Battelli","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Chen, J., Liu, J., Gu, Z., Fan, J., Lei, S., Zhang, Q., Pan, K., and Wang, Y. (2024). Adherence to oxidative balance score is inversely associated with the prevalence of stroke: Results from National Health and Nutrition Examination Survey 1999\u20132018. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1348011"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Yu, H., Chen, X., Guo, X., Chen, D., Jiang, L., Qi, Y., Shao, J., Tao, L., Hang, J., and Lu, G. (2023). The clinical value of serum xanthine oxidase levels in patients with acute ischemic stroke. Redox Biol., 60.","DOI":"10.1016\/j.redox.2023.102623"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e695","DOI":"10.1016\/j.wneu.2024.02.014","article-title":"Machine Learning-Based Clinical Prediction Models for Acute Ischemic Stroke Based on Serum Xanthine Oxidase Levels","volume":"184","author":"Chen","year":"2024","journal-title":"World Neurosurg."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kim, J., Lee, S.Y., Lee, J., Yoon, S., Kim, E.G., Lee, E., Kim, N., Lee, S., Gym, H., and Park, S.I. (2024). Effects of uric acid on ischemic diseases, stratified by lipid levels: A drug-target, nonlinear Mendelian randomization study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-51724-1"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Otani, N., Hoshiyama, E., Ouchi, M., Takekawa, H., and Suzuki, K. (2023). Uric acid and neurological disease: A narrative review. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1164756"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Singh, J.A., and Yu, S. (2016). Allopurinol and the risk of stroke in older adults receiving medicare. BMC Neurol., 16.","DOI":"10.1186\/s12883-016-0692-2"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"106407","DOI":"10.1016\/j.phrs.2022.106407","article-title":"Chronic kidney disease: Which role for xanthine oxidoreductase activity and products?","volume":"184","author":"Polito","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0079-6123(10)83010-9","article-title":"Pathophysiological roles for purines: Adenosine, caffeine and urate","volume":"183","author":"Morelli","year":"2010","journal-title":"Prog. Brain Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Matsumura, N., and Aoyama, K. (2023). Glutathione-Mediated Neuroprotective Effect of Purine Derivatives. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713067"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s13311-016-0497-4","article-title":"Urate as a Marker of Risk and Progression of Neurodegenerative Disease","volume":"14","author":"Paganoni","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_87","unstructured":"Parkinson Study Group SURE-PD Investigators (2014). Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: A randomized clinical trial. JAMA Neurol., 71, 141\u2013150."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e1328","DOI":"10.1212\/WNL.0000000000008194","article-title":"Parkinson Study Group SURE-PD Investigators, Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial","volume":"93","author":"Schwarzschild","year":"2019","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Basile, M.S., Bramanti, P., and Mazzon, E. (2022). Inosine in Neurodegenerative Diseases: From the Bench to the Bedside. Molecules, 27.","DOI":"10.3390\/molecules27144644"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1002\/acn3.671","article-title":"Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis","volume":"5","author":"Nicholson","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1002\/mus.27807","article-title":"Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis","volume":"67","author":"Walk","year":"2023","journal-title":"Muscle Nerve"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1177\/135245850100700507","article-title":"Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease","volume":"7","author":"Spitsin","year":"2001","journal-title":"Mult. Scler."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1089\/acm.2008.0513","article-title":"The treatment of multiple sclerosis with inosine","volume":"15","author":"Markowitz","year":"2009","journal-title":"J. Altern. Complement. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1161\/STROKEAHA.115.009960","article-title":"Uric Acid Therapy Improves Clinical Outcome in Women with Acute Ischemic Stroke","volume":"46","author":"Llull","year":"2015","journal-title":"Stroke"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1002\/mds.29209","article-title":"Uric Acid in Parkinson\u2019s Disease: What Is the Connection?","volume":"37","author":"Seifar","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Johnson, T.A., Jinnah, H.A., and Kamatani, N. (2019). Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00098"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Sekine, M., Fujiwara, M., Okamoto, K., Ichida, K., Nagata, K., Hille, R., and Nishino, T. (2024). Significance and amplification methods of the purine salvage pathway in human brain cells. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107524"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e21576","DOI":"10.1097\/MD.0000000000021576","article-title":"Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine","volume":"99","author":"Watanabe","year":"2020","journal-title":"Medicine"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.2174\/0929867323666160725091915","article-title":"Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme","volume":"23","author":"Battelli","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s12035-020-02115-w","article-title":"Uric Acid Neuroprotection Associated to IL-6\/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke","volume":"58","author":"Torregrosa","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Bolognesi, A., Bortolotti, M., Battelli, M.G., and Polito, L. (2024). Gender Influence on XOR Activities and Related Pathologies: A Narrative Review. Antioxidants, 13.","DOI":"10.3390\/antiox13020211"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Mijailovic, N.R., Vesic, K., and Borovcanin, M.M. (2022). The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.828476"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1007\/s12035-024-04260-y","article-title":"Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes","volume":"62","author":"Kumari","year":"2025","journal-title":"Mol. Neurobiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/4\/483\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:08Z","timestamp":1760030168000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/4\/483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":103,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["antiox14040483"],"URL":"https:\/\/doi.org\/10.3390\/antiox14040483","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]}}}