{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:38:17Z","timestamp":1787755097717,"version":"build-2784847793"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Multiple Sklerose Gesellschaft (DMSG) Ortsvereinigung (OV) D\u00fcsseldorf"},{"name":"Umgebung e.V."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS), an auto-immune disease of the central nervous system (CNS) with inflammatory and neurodegenerative properties, remains an insufficiently understood disease despite more than 150 years of research. In contrast to diseases from other medical fields such as, for instance, oncology, a description of its clinical and non-clinical features based on readouts such as biomarkers is still in its infancy. While, in this regard, neurofilament light chain (NfL) seems to be a promising new tool, the significant intra- and interindividual variation of this serological marker somewhat limits its widespread applicability in everyday clinical reality. This has sparked novel studies in which glial fibrillary acidic protein (GFAP) was proposed as an on-top marker serving to improve overall specificity. In this context, it was found that MS disease progression was significantly more often associated with increased levels of both NfL and GFAP compared to increased NfL levels alone. This highlights the complexity of the disease while also emphasizing the potential benefits of introducing additional markers to enhance current options. We propose that nitrosative stress markers, such as nitrate, nitrite, and nitrotyrosine (3NT), could serve this purpose effectively.<\/jats:p>","DOI":"10.3390\/ijms26073412","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T20:43:17Z","timestamp":1745440997000},"page":"3412","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Do Nitrosative Stress Molecules Hold Promise as Biomarkers for Multiple Sclerosis?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0682-9859","authenticated-orcid":false,"given":"Moritz","family":"F\u00f6rster","sequence":"first","affiliation":[{"name":"Department of Neurology, Kliniken Maria Hilf GmbH, Academic Teaching Hospital of the RWTH Aachen University Hospital, 41063 M\u00f6nchengladbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8901-5572","authenticated-orcid":false,"given":"Saskia","family":"R\u00e4uber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kliniken Maria Hilf GmbH, Academic Teaching Hospital of the RWTH Aachen University Hospital, 41063 M\u00f6nchengladbach, Germany"},{"name":"Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-4405","authenticated-orcid":false,"given":"Lars","family":"Wojtecki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"},{"name":"Department of Neurology and Neurorehabilitation, Hospital Zum Heiligen Geist, Academic Teaching Hospital of the Heinrich Heine University D\u00fcsseldorf, 47906 Kempen, Germany"},{"name":"Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-3501","authenticated-orcid":false,"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kremer","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurorehabilitation, Hospital Zum Heiligen Geist, Academic Teaching Hospital of the Heinrich Heine University D\u00fcsseldorf, 47906 Kempen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1093\/ije\/dyac234","article-title":"Association between exposure to combustion-related air pollution and multiple sclerosis risk","volume":"52","author":"Segersson","year":"2023","journal-title":"Int. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/nrmicro.2017.112","article-title":"The microbiota maintains oxygen balance in the gut","volume":"15","author":"Vacca","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-022-01148-1","article-title":"The gut microbiota in multiple sclerosis varies with disease activity","volume":"15","author":"Thirion","year":"2023","journal-title":"Genome Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Flores, J.A., Antonio, J.M., Suntornsaratoon, P., Meadows, V., Bandyopadhyay, S., Han, J., Singh, R., Balasubramanian, I., Upadhyay, R., and Liu, Y. (2024). The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107614"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"F\u00f6rster, M., Nelke, C., R\u00e4uber, S., Lassmann, H., Ruck, T., Sormani, M.P., Signori, A., Hartung, H.-P., K\u00fcry, P., and Meuth, S.G. (2021). Nitrosative Stress Molecules in Multiple Sclerosis: A Meta-Analysis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121899"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"R\u00e4uber, S., F\u00f6rster, M., Sch\u00fcller, J., Willison, A., Golombeck, K.S., Schroeter, C.B., Oeztuerk, M., Jansen, R., Huntemann, N., and Nelke, C. (2024). The Use of Nitrosative Stress Molecules as Po-tential Diagnostic Biomarkers in Multiple Sclerosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25020787"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nrcardio.2017.224","article-title":"Nitric oxide signalling in cardiovascular health and disease","volume":"15","author":"Farah","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/nrn2214","article-title":"Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity","volume":"8","author":"Calabrese","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.8100368","article-title":"Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus","volume":"260","author":"Zhuo","year":"1993","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9191","DOI":"10.1073\/pnas.90.19.9191","article-title":"Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats","volume":"90","author":"Bon","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.neuint.2004.03.021","article-title":"Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation","volume":"45","author":"Contestabile","year":"2004","journal-title":"Neurochem. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0378-4274(95)03557-5","article-title":"Nitric oxide (NO) protects against cellular damage by reactive oxygen species","volume":"82\u201383","author":"Wink","year":"1995","journal-title":"Toxicol. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, Y., Hong, F., and Yang, S. (2022). Roles of Nitric Oxide in Brain Ischemia and Reperfusion. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084243"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/ana.410360515","article-title":"Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains","volume":"36","author":"Dawson","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1515\/revneuro-2017-0033","article-title":"Insights in pathogenesis of multiple sclerosis: Nitric oxide may induce mitochondrial dysfunction of oligodendrocytes","volume":"29","author":"Lan","year":"2017","journal-title":"Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1124\/pr.108.000547","article-title":"Cerebral blood flow regulation by nitric oxide: Recent advances","volume":"61","author":"Toda","year":"2009","journal-title":"Pharmacol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.freeradbiomed.2007.04.026","article-title":"Methods to detect nitric oxide and its metabolites in biological samples","volume":"43","author":"Bryan","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6282","DOI":"10.1007\/s12035-017-0843-5","article-title":"Multiple Immune-Inflammatory and Oxidative and Nitrosative Stress Pathways Explain the Frequent Presence of Depression in Multiple Sclerosis","volume":"55","author":"Morris","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1161\/01.RES.73.6.1121","article-title":"Metabolism and excretion of nitric oxide in humans. An experimental and clinical study","volume":"73","author":"Wennmalm","year":"1993","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1124\/pr.120.019240","article-title":"The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway","volume":"72","author":"Kapil","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/01.wno.0000221652.56574.99","article-title":"Nitric Oxide in Optic Neuritis and Multiple Sclerosis","volume":"26","author":"Chuman","year":"2006","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/01.wno.0000223266.48447.1b","article-title":"Immunohistochemical evidence of inducible nitric oxide synthase and nitrotyrosine in a case of clinically isolated optic neuritis","volume":"26","author":"Tsoi","year":"2006","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Varhaug, K.N., Torkildsen, \u00d8., Myhr, K.-M., and Vedeler, C.A. (2019). Neurofilament light chain as a biomarker in multiple sclerosis. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00338"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5312","DOI":"10.1073\/pnas.92.12.5312","article-title":"Local nitric oxide production in viral and autoimmune diseases of the central nervous system","volume":"92","author":"Hooper","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1002\/jnr.10408","article-title":"Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels","volume":"70","author":"Calabrese","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1046\/j.1471-4159.1996.67052013.x","article-title":"Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF","volume":"67","author":"Rosengren","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Thebault, S., Abdoli, M., Fereshtehnejad, S.-M., Tessier, D., Tabard-Cossa, V., and Freedman, M.S. (2020). Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67504-6"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1136\/jnnp-2018-319190","article-title":"Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: A meta-analysis of case\u2013control studies","volume":"90","author":"Martin","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/s12974-018-1249-7","article-title":"Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis","volume":"15","author":"Tisell","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Freedman, M.S., Gnanapavan, S., Booth, R.A., Calabresi, P.A., Khalil, M., Kuhle, J., Lycke, J., and Olsson, T. (2024). Guidance for use of neurofilament light chain as a cerebrospinal fluid and blood biomarker in multiple sclerosis management. EBioMedicine, 101.","DOI":"10.1016\/j.ebiom.2024.104970"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/acn3.51060","article-title":"Temporal association of sNfL and gad-enhancing lesions in multiple sclerosis","volume":"7","author":"Rosso","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis","volume":"81","author":"Disanto","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.4155\/bio-2019-0163","article-title":"Establishment of neurofilament light chain Simoa assay in cerebrospinal fluid and blood","volume":"11","author":"Hendricks","year":"2019","journal-title":"Bioanalysis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1001\/jamaneurol.2018.3746","article-title":"Association of Cerebrospinal Fluid Neuro-filament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders","volume":"76","author":"Olsson","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41392-023-01628-9","article-title":"Astrocytes in human central nervous system diseases: A frontier for new therapies","volume":"8","author":"Verkhratsky","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Correale, J., and Farez, M.F. (2015). The Role of Astrocytes in Multiple Sclerosis Progression. Front. Neurol., 6.","DOI":"10.3389\/fneur.2015.00180"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/acn3.51969","article-title":"Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis","volume":"11","author":"Abdelhak","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1002\/acn3.52187","article-title":"Serum glial fibrillary acidic protein predicts disease progression in multiple sclerosis","volume":"11","author":"Madill","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1001\/jamaneurol.2024.0017","article-title":"Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis","volume":"81","author":"Cross","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Abdelhak, A., Huss, A., Kassubek, J., Tumani, H., and Otto, M. (2018). Serum GFAP as a biomarker for disease severity in multiple sclerosis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-33158-8"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1001\/jamaneurol.2022.5250","article-title":"Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis","volume":"80","author":"Meier","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ayrignac, X., Le Bars, E., Duflos, C., Hirtz, C., Maceski, A.M., Carra-Dalli\u00e8re, C., Charif, M., Pinna, F., Prin, P., and de Champfleur, N.M. (2020). Serum GFAP in multiple sclerosis: Correlation with disease type and MRI markers of disease severity. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67934-2"},{"key":"ref_43","first-page":"101009","article-title":"Fluid biomarkers in multiple sclerosis: From current to future applications","volume":"44","author":"Gaetani","year":"2024","journal-title":"Lancet Reg. Health\u2014Eur."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3412\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:10:47Z","timestamp":1760029847000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,5]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073412"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073412","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,5]]}}}