{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:46:50Z","timestamp":1759798010399,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Neurodegeneration is present from the earliest stages of multiple sclerosis [MS], and oxidative stress together with mitochondrial dysfunction are key contributors to neuronal injury and disease progression. Objective: To investigate the role of the antioxidant enzyme paraoxonase 1 (PON1) and serum asymmetric dimethylarginine (ADMA) levels in MS across different disease subtypes and immunomodulatory treatments. Methods: Serum lipid levels and PON1 activity were measured and compared by disease subtype and treatment in a single-center MS cohort (N = 262; CIS = 10, RRMS = 208, PPMS = 19, SPMS = 25; 110 untreated, 152 treated) and in 91 healthy controls. ADMA levels were assessed in sera from 79 MS patients (19 untreated, 60 treated) and 31 age-matched controls. Results: Median serum paraoxonase (PON) and arylesterase (ARE) activity levels were 83.8 and 127.2 IU\/L in MS patients versus 85.9 and 136.9 IU\/L in controls, with no significant difference for PON (p = 0.191) but a significant reduction in ARE [p = 0.003]. PON activity differed significantly among disease subtypes (p = 0.023), with the highest levels in CIS. PON and ARE activity also varied across treatment groups (p = 0.038 and p = 0.034, respectively), with longitudinal analysis indicating a measurable effect of immunomodulatory therapy on PON activity at 10 years (p = 0.0136). Significant differences in enzyme activity were observed between untreated and interferon-treated patients (PON p = 0.0055, ARE p = 0.0001), with trends toward differences in ARE under natalizumab and fingolimod. ADMA levels were lower in MS patients than controls (p &lt; 0.0001) and differed among treatment subgroups (natalizumab, dimethyl fumarate, glatiramer acetate, untreated RRMS). Conclusions: PON1 activity and ADMA levels differ between MS subgroups and under immunomodulatory treatments. Long-term therapy was associated with increased PON1 activity, while highly effective immunomodulators reduced ADMA levels. These changes may contribute to the treatment-related reduction in disease activity and attenuation of neurodegenerative processes in MS.<\/jats:p>","DOI":"10.3390\/ijms26199728","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"9728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of Paraoxonase 1 Activity and Asymmetric Dimethylarginine by Immunomodulatory Therapies in Multiple Sclerosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8433-3485","authenticated-orcid":false,"given":"Lilla","family":"Racz","sequence":"first","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5303-3082","authenticated-orcid":false,"given":"Hajnalka","family":"Lorincz","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ildiko","family":"Seres","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-1057","authenticated-orcid":false,"given":"Laszlo","family":"Kardos","sequence":"additional","affiliation":[{"name":"Clinical Department of Infectious Diseases, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyorgy","family":"Paragh","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-3209","authenticated-orcid":false,"given":"Tunde","family":"Csepany","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e01598","DOI":"10.1002\/brb3.1598","article-title":"Epidemiology of multiple sclerosis in Central Europe, update from Hungary","volume":"10","author":"Biernacki","year":"2020","journal-title":"Brain Behav."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1212\/WNL.0000000000000560","article-title":"Defining the clinical course of multiple sclerosis: The 2013 revisions","volume":"83","author":"Lublin","year":"2014","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/brain\/awq076","article-title":"Evidence for a two-stage disability progression in multiple sclerosis","volume":"133","author":"Leray","year":"2010","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"University of California, San Francisco MS-EPIC Team, Cree, B.A.C., Hollenbach, J.A., Bove, R., Kirkish, G., Sacco, S., Caverzasi, E., Bischof, A., Gundel, T., and Msc, A.H.Z. (2019). Silent progression in disease activity-free relapsing multiple sclerosis. Ann. Neurol., 85, 653\u2013666.","DOI":"10.1002\/ana.25463"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ana.1032","article-title":"Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis","volume":"50","author":"McDonald","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S1474-4422(22)00289-7","article-title":"Multiple sclerosis progression: Time for a new mechanism-driven framework","volume":"22","author":"Kuhlmann","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Trofin, D.M., Sardaru, D.P., Trofin, D., Onu, I., Tutu, A., Onu, A., Onit\u0103, C., Galaction, A.I., and Matei, D.V. (2025). Oxidative Stress in Brain Function. Antioxidants, 14.","DOI":"10.3390\/antiox14030297"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Khalaf, F.K., Connolly, J., Khatib-Shahidi, B., Albehadili, A., Tassavvor, I., Ranabothu, M., Eid, N., Dube, P., Khouri, S.J., and Malhotra, D. (2023). Paraoxonases at the Heart of Neurological Disorders. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24086881"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Reichert, C.O., Levy, D., and Bydlowski, S.P. (2021). Paraoxonase Role in Human Neurodegenerative Diseases. Antioxidants, 10.","DOI":"10.3390\/antiox10010011"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1159\/000045161","article-title":"The serum paraoxonase activity in patients with chronic renal failure and hyperlipidemia","volume":"80","author":"Paragh","year":"1998","journal-title":"Nephron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1196\/annals.1422.009","article-title":"Reduced paraoxonase1 activity is a risk for atherosclerosis in patients with systemic lupus erythematosus","volume":"1108","author":"Kiss","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1177\/1352458508098371","article-title":"Paraoxonase 1 activity in different types of multiple sclerosis","volume":"15","author":"Beltowski","year":"2009","journal-title":"Mult. Scler."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/intimm\/dxq045","article-title":"Decreased human paraoxonase-1 activity in patients with Sj\u00f6gren\u2019s syndrome","volume":"22","author":"Harangi","year":"2010","journal-title":"Int. Immunol."},{"key":"ref_15","first-page":"1126","article-title":"The human serum paraoxonase\/arylesterase polymorphism","volume":"35","author":"Eckerson","year":"1983","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1097\/00008571-199912000-00009","article-title":"Determination of paraoxonase (PON1) status requires more than genotyping","volume":"9","author":"Richter","year":"1999","journal-title":"Pharmacogenetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/1352458507082061","article-title":"Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis","volume":"14","author":"Rejdak","year":"2008","journal-title":"Mult. Scler."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1093\/rheumatology\/keu349","article-title":"Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: A 6 year follow-up study","volume":"54","author":"Sandoo","year":"2015","journal-title":"Rheumatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.freeradbiomed.2014.12.002","article-title":"Asymmetric dimethylarginine exacerbates A\u03b2-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease","volume":"79","author":"Luo","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1191\/1352458505ms1240oa","article-title":"Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: A relationship with paraoxonase activity","volume":"11","author":"Ferretti","year":"2005","journal-title":"Mult. Scler."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1007\/s00726-015-2015-0","article-title":"Serum and cerebrospinal fluid concentrations of homoarginine, arginine, asymmetric and symmetric dimethylarginine, nitrite and nitrate in patients with multiple sclerosis and neuromyelitis optica","volume":"47","author":"Haghikia","year":"2015","journal-title":"Amino Acids"},{"key":"ref_22","first-page":"679","article-title":"An anti-oxidant, serum paraoxonase1 activity in multiple sclerosis","volume":"21","author":"Racz","year":"2014","journal-title":"Eur. J. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.jocn.2012.09.020","article-title":"Serum paraoxonase and arylesterase activity and oxidative status in patients with multiple sclerosis","volume":"20","author":"Kirbas","year":"2013","journal-title":"J. Clin. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.clinbiochem.2011.04.010","article-title":"Lack of association between paraoxonase 1 Q192R polymorphism and multiple sclerosis in relapse phase: A case-control study","volume":"44","author":"Moghtaderi","year":"2011","journal-title":"Clin. Biochem."},{"key":"ref_25","first-page":"E047","article-title":"Paraoxonase1 activity and phenotype distribution in multiple sclerosis","volume":"69","author":"Yaman","year":"2016","journal-title":"Ideggyogy. Szle."},{"key":"ref_26","first-page":"1654754","article-title":"Cladribine Treatment Improved Homocysteine Metabolism and Increased Total Serum Antioxidant Activity in Secondary Progressive Multiple Sclerosis Patients","volume":"14","author":"Beltowski","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.exger.2003.08.001","article-title":"Study of factors influencing the decreased HDL associated PON1 activity with aging","volume":"39","author":"Seres","year":"2004","journal-title":"Exp. Gerontol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.exger.2007.04.006","article-title":"Effect of PON1 polymorphism on HDL antioxidant potential is blunted with aging","volume":"42","author":"Cherki","year":"2007","journal-title":"Exp. Gerontol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"577497","DOI":"10.1016\/j.jneuroim.2021.577497","article-title":"Serum ADMA levels were positively correlated with EDSS scores in patients with multiple sclerosis","volume":"353","author":"Onmaz","year":"2021","journal-title":"J. Neuroimmunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Monti, L., Morbidelli, L., Bazzani, L., and Rossi, A. (2017). Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis. Biomark. Insights, 12.","DOI":"10.1177\/1177271917712514"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s11306-020-1648-5","article-title":"Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry","volume":"16","author":"Carlsson","year":"2020","journal-title":"Metabolomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.clineuro.2016.07.001","article-title":"Effectiveness and safety of natalizumab in real-world clinical practice: Review of observational studies","volume":"149","author":"Sindic","year":"2016","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1136\/jnnp-2022-329223","article-title":"Superior effects of natalizumab versus other DMTs on patient-reported outcomes in people with multiple sclerosis","volume":"93","author":"Chen","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/13696998.2023.2293379","article-title":"Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom","volume":"27","author":"Spelman","year":"2024","journal-title":"J. Med. Econ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_36","first-page":"465","article-title":"Can a physician predict the clinical response to first-line immunomodulatory treatment in relapsing-remitting multiple sclerosis?","volume":"8","author":"Mezei","year":"2012","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0009-8981(02)00216-4","article-title":"HDL3-related decreased serum paraoxonase (PON) activity in uremic patients: Comparison with the PON1 allele polymorphism","volume":"324","author":"Schiavon","year":"2002","journal-title":"Clin. Chim. Acta"},{"key":"ref_38","first-page":"2338","article-title":"The polymorphic paraoxonase\/arylesterase isozymes of human serum","volume":"43","author":"Eckerson","year":"1984","journal-title":"Fed. Proc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1515\/CCLM.2004.257","article-title":"Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay","volume":"42","author":"Schulze","year":"2004","journal-title":"Clin. Chem. Lab. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9728\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:16:35Z","timestamp":1759763795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,6]]},"references-count":39,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199728"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199728","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,6]]}}}