{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:52:22Z","timestamp":1781783542388,"version":"3.54.5"},"reference-count":182,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Multiple sclerosis (MS) is a neuro-inflammatory disease characterized by demyelination in the central nervous system (CNS). Although a substantial endogenous capacity for remyelination has been demonstrated, this process is frequently incomplete and exhibits marked intra- and inter-individual heterogeneity. Several factors influence the extent of spontaneous myelin regeneration, including age, sex, disease course, and lesion localization. Oligodendrocytes (OL), derived from oligodendrocyte progenitor cells (OPCs), are the principal myelinating cells of the CNS. The regenerative cascade involves several key stages, including OPC activation, recruitment, differentiation into oligodendrocytes (OL), and myelin deposition. This process is orchestrated in a spatiotemporal manner by a complex interplay of intracellular signaling pathways, genetic determinants, and dynamic microenvironmental cues, which together balance inhibitory and pro-remyelinating influences. Several lines of evidence indicate that chronically demyelinated axons are vulnerable to degeneration, whereas successful remyelination may confer neuroprotection. These observations underscore remyelination as a promising neuroprotective therapeutic target for preventing or slowing disability progression in MS, a condition in which gradual neuroaxonal degeneration is believed to underlie irreversible disability progression. In this review, we aim to bridge the gap between fundamental biological mechanisms of remyelination and their clinical relevance. We examine recent advances in in vivo techniques for assessing remyelination and discuss how these measures correlate with clinical and disability outcomes. In addition, we review recent clinical trials of remyelination-promoting therapies and analyze the challenges that have limited their advancement beyond phase II. Overall, we seek to provide a comprehensive overview of the remyelination process from bench to bedside, highlighting both the obstacles and the therapeutic potential of remyelination strategies in MS.<\/jats:p>","DOI":"10.3390\/medicina62061183","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:25:34Z","timestamp":1781778334000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myelin Repair as a Neuroprotective Strategy for Multiple Sclerosis: From Bench to Bedside"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6279-2096","authenticated-orcid":false,"given":"Tima","family":"Battah","sequence":"first","affiliation":[{"name":"Medical School, European University Cyprus, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilios","family":"Mastorodemos","sequence":"additional","affiliation":[{"name":"Mesogeios Diagnostic Center,  71306 Heraklion,  Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5155-1465","authenticated-orcid":false,"given":"Erich","family":"Struecker","sequence":"additional","affiliation":[{"name":"Medical School, European University Cyprus, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimos Dimitrios","family":"Mitsikostas","sequence":"additional","affiliation":[{"name":"1st Neurology Department, Eginition University Hospital, National and Kapodistrian University of Athens,   15784 Athens, Attica, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-7740","authenticated-orcid":false,"given":"Dimitrios","family":"Papadopoulos","sequence":"additional","affiliation":[{"name":"Medical School, European University Cyprus, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","first-page":"169","article-title":"\u00dcber Diskontinuierliche Zerfallsprozesse an Der Peripheren Nervenfaser","volume":"1","author":"Stransky","year":"1903","journal-title":"J. Psychol. Neurol."},{"key":"ref_2","unstructured":"Marburg, O. (1906). Die Sogenannte Akute Multiple Sklerose, \u0420\u0438\u043fo\u043b \u041a\u043b\u0430\u0441\u0441\u0438\u043a."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/ana.410330203","article-title":"Multiple Sclerosis: Remyelination of Nascent Lesions: Remyelination of Nascent Lesions","volume":"33","author":"Prineas","year":"1993","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/ana.410350111","article-title":"Oligodendrocytes in the Early Course of Multiple Sclerosis","volume":"35","author":"Schmied","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0074-7742(07)79026-8","article-title":"Remyelination In Multiple Sclerosis","volume":"79","author":"Chari","year":"2007","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.expneurol.2016.06.005","article-title":"The History of Myelin","volume":"283","author":"Boullerne","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1093\/brain\/88.5.937","article-title":"Electron Microscopic Features of Multiple Sclerosis Lesions","volume":"88","year":"1965","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a020479","DOI":"10.1101\/cshperspect.a020479","article-title":"Oligodendrocytes: Myelination and Axonal Support","volume":"8","author":"Simons","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Han, S., Gim, Y., Jang, E.-H., and Hur, E.-M. (2022). Functions and Dysfunctions of Oligodendrocytes in Neurodegenerative Diseases. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.1083159"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nn1620","article-title":"Competing Waves of Oligodendrocytes in the Forebrain and Postnatal Elimination of an Embryonic Lineage","volume":"9","author":"Kessaris","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13024-024-00742-8","article-title":"The Interplay of Inflammation and Remyelination: Rethinking MS Treatment with a Focus on Oligodendrocyte Progenitor Cells","volume":"19","author":"Zveik","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/nrn2480","article-title":"Remyelination in the CNS: From Biology to Therapy","volume":"9","author":"Franklin","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/00005072-199301000-00007","article-title":"The Potential for Oligodendrocyte Proliferation During Demyelinating Disease","volume":"52","author":"Prayoonwiwat","year":"1993","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.ajpath.2015.11.005","article-title":"Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination Following Toxin-Induced Spinal Cord Demyelination","volume":"186","author":"Crawford","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1097\/00005072-199711000-00003","article-title":"Identification of Post-Mitotic Oligodendrocytes Incapable of Remyelination within the Demyelinated Adult Spinal Cord","volume":"56","author":"Keirstead","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.neuron.2023.03.031","article-title":"Remyelination by Surviving Oligodendrocytes Is Inefficient in the Inflamed Mammalian Cortex","volume":"111","author":"Mezydlo","year":"2023","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1365-2990.1996.tb00895.x","article-title":"Failure to Achieve Remyelination of Demyelinated Rat Axons Following Transplantation of Glial Cells Obtained from the Adult Human Brain","volume":"22","author":"Targett","year":"1996","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/s41586-018-0842-3","article-title":"Dynamics of Oligodendrocyte Generation in Multiple Sclerosis","volume":"566","author":"Yeung","year":"2019","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/s41593-020-0637-3","article-title":"Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes","volume":"23","author":"Bacmeister","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E11807","DOI":"10.1073\/pnas.1808064115","article-title":"The Adult Oligodendrocyte Can Participate in Remyelination","volume":"115","author":"Duncan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1523\/JNEUROSCI.22-07-02451.2002","article-title":"The Age-Related Decrease in CNS Remyelination Efficiency Is Attributable to an Impairment of Both Oligodendrocyte Progenitor Recruitment and Differentiation","volume":"22","author":"Sim","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/362453a0","article-title":"Repair of Demyelinated Lesions by Transplantation of Purified 0-2A Progenitor Cells","volume":"362","author":"Groves","year":"1993","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/mdb2.70007","article-title":"Oligodendrocyte Precursor Cells in Demyelination Repair: Mechanisms, Crosstalk, and Therapeutic Frontiers","volume":"1","author":"Gao","year":"2025","journal-title":"Med. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113574","DOI":"10.1016\/j.celrep.2023.113574","article-title":"Microglia Promote Remyelination Independent of Their Role in Clearing Myelin Debris","volume":"42","author":"Baaklini","year":"2023","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/brain\/aws262","article-title":"Astrocytes Regulate Myelin Clearance through Recruitment of Microglia during Cuprizone-Induced Demyelination","volume":"136","author":"Skripuletz","year":"2013","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.stem.2010.04.002","article-title":"CNS-Resident Glial Progenitor\/Stem Cells Produce Schwann Cells as Well as Oligodendrocytes during Repair of CNS Demyelination","volume":"6","author":"Zawadzka","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"200352","DOI":"10.1098\/rsob.200352","article-title":"Schwann Cell Remyelination of the Central Nervous System: Why Does It Happen and What Are the Benefits?","volume":"11","author":"Chen","year":"2021","journal-title":"Open Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.expneurol.2005.10.033","article-title":"Axon Loss Is Responsible for Chronic Neurological Deficit Following Inflammatory Demyelination in the Rat","volume":"197","author":"Papadopoulos","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/0022-510X(91)90064-E","article-title":"Extensive Proliferation of Peripheral Type Myelin in Necrotic Spinal Cord Lesions of Multiple Sclerosis","volume":"102","author":"Yamamoto","year":"1991","journal-title":"J. Neurol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1365-2990.1976.tb00559.x","article-title":"Invasion of Schwann Cells into the Spinal Cord of the Rat Following Local Injections of Lysolecithin","volume":"2","author":"Blakemore","year":"1976","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1177\/0271678X221137762","article-title":"The Roles of Microglia and Astrocytes in Myelin Phagocytosis in the Central Nervous System","volume":"43","author":"Xu","year":"2023","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1093\/brain\/awab059","article-title":"The Extracellular Matrix as Modifier of Neuroinflammation and Remyelination in Multiple Sclerosis","volume":"144","author":"Ghorbani","year":"2021","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10571-016-0359-y","article-title":"pERK1\/2 Peripheral Recruitment and Filopodia Protrusion Augment Oligodendrocyte Progenitor Cell Migration: Combined Effects of PDGF-A and Fibronectin","volume":"37","author":"Tripathi","year":"2017","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"134916","DOI":"10.1016\/j.neulet.2020.134916","article-title":"Neuron-Oligodendroglia Interactions: Activity-Dependent Regulation of Cellular Signaling","volume":"727","author":"Thornton","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Domingues, H.S., Portugal, C.C., Socodato, R., and Relvas, J.B. (2016). Oligodendrocyte, Astrocyte, and Microglia Crosstalk in Myelin Development, Damage, and Repair. Front. Cell Dev. Biol., 4.","DOI":"10.3389\/fcell.2016.00071"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.1523\/JNEUROSCI.4930-10.2011","article-title":"Inhibition of CNS Remyelination by the Presence of Semaphorin 3A","volume":"31","author":"Syed","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.ajpath.2013.06.004","article-title":"Full-Length and Fragmented Netrin-1 in Multiple Sclerosis Plaques Are Inhibitors of Oligodendrocyte Precursor Cell Migration","volume":"183","author":"Bin","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/361258a0","article-title":"Proliferation of Oligodendrocyte Precursor Cells Depends on Electrical Activity in Axons","volume":"361","author":"Barres","year":"1993","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Moura, D.M.S., Brennan, E.J., Brock, R., and Cocas, L.A. (2022). Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.779125"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.celrep.2018.09.066","article-title":"In Vivo Regulation of Oligodendrocyte Precursor Cell Proliferation and Differentiation by the AMPA-Receptor Subunit GluA2","volume":"25","author":"Chen","year":"2018","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/nature04302","article-title":"NMDA Receptors Are Expressed in Oligodendrocytes and Activated in Ischaemia","volume":"438","author":"Cavelier","year":"2005","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7728","DOI":"10.1038\/s41598-019-44050-4","article-title":"Enhanced Remyelination during Late Pregnancy: Involvement of the GABAergic System","volume":"9","author":"Kalakh","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tiane, A., Schepers, M., Rombaut, B., Hupperts, R., Prickaerts, J., Hellings, N., Van Den Hove, D., and Vanmierlo, T. (2019). From OPC to Oligodendrocyte: An Epigenetic Journey. Cells, 8.","DOI":"10.3390\/cells8101236"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hornig, J., Fr\u00f6b, F., Vogl, M.R., Hermans-Borgmeyer, I., Tamm, E.R., and Wegner, M. (2013). The Transcription Factors Sox10 and Myrf Define an Essential Regulatory Network Module in Differentiating Oligodendrocytes. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003907"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.celrep.2016.03.060","article-title":"Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage","volume":"15","author":"Moyon","year":"2016","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1007\/s00018-021-03927-2","article-title":"DNA Methylation Regulates the Expression of the Negative Transcriptional Regulators ID2 and ID4 during OPC Differentiation","volume":"78","author":"Tiane","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1523\/JNEUROSCI.0010-22.2022","article-title":"mTORC2 Loss in Oligodendrocyte Progenitor Cells Results in Regional Hypomyelination in the Central Nervous System","volume":"43","author":"Dahl","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wen, X., Jiao, L., and Tan, H. (2022). MAPK\/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031464"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/s12035-013-8584-6","article-title":"Wnt Signaling in Remyelination in Multiple Sclerosis: Friend or Foe?","volume":"49","author":"Xie","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1523\/JNEUROSCI.4270-10.2011","article-title":"Wnt\/\u03b2-Catenin Signaling Is an Essential and Direct Driver of Myelin Gene Expression and Myelinogenesis","volume":"31","author":"Tawk","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jneuroim.2009.08.010","article-title":"Notch: A New Player in MS Mechanisms","volume":"218","author":"Selmaj","year":"2010","journal-title":"J. Neuroimmunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sun, Y., Ji, J., Zha, Z., Zhao, H., Xue, B., Jin, L., and Wang, L. (2021). Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.628209"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s40263-013-0068-8","article-title":"Blocking LINGO-1 as a Therapy to Promote CNS Repair: From Concept to the Clinic","volume":"27","author":"Mi","year":"2013","journal-title":"CNS Drugs"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Rashidbenam, Z., Ozturk, E., Pagnin, M., Theotokis, P., Grigoriadis, N., and Petratos, S. (2023). How Does Nogo Receptor Influence Demyelination and Remyelination in the Context of Multiple Sclerosis?. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1197492"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.conb.2016.04.013","article-title":"The Cell Biology of CNS Myelination","volume":"39","author":"Hughes","year":"2016","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/j.1471-4159.1992.tb09316.x","article-title":"Morphometric Analysis of Normal, Mutant, and Transgenic CNS: Correlation of Myelin Basic Protein Expression to Myelinogenesis","volume":"58","author":"Shine","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1093\/brain\/awn076","article-title":"From Fish to Man: Understanding Endogenous Remyelination in Central Nervous System Demyelinating Diseases","volume":"131","author":"Williams","year":"2008","journal-title":"Brain"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1586\/14737175.2016.1116387","article-title":"Remyelination Strategies in Multiple Sclerosis: A Critical Reflection","volume":"16","author":"Kipp","year":"2016","journal-title":"Expert Rev. Neurother."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Baaklini, C.S., Rawji, K.S., Duncan, G.J., Ho, M.F.S., and Plemel, J.R. (2019). Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00225"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1136\/jnnp.41.5.408","article-title":"Conduction through Demyelinated Plaques in Multiple Sclerosis: Computer Simulations of Facilitation by Short Internodes","volume":"41","author":"Waxman","year":"1978","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/nen.0b013e3181462841","article-title":"Sodium Channel Expression Within Chronic Multiple Sclerosis Plaques","volume":"66","author":"Black","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gacem, N., and Nait-Oumesmar, B. (2021). Oligodendrocyte Development and Regenerative Therapeutics in Multiple Sclerosis. Life, 11.","DOI":"10.3390\/life11040327"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.stem.2020.03.017","article-title":"Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis","volume":"26","author":"Neumann","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1001\/archneur.60.8.1073","article-title":"Remyelinated Lesions in Multiple Sclerosis: Magnetic Resonance Image Appearance","volume":"60","author":"Barkhof","year":"2003","journal-title":"Arch. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1093\/brain\/awl217","article-title":"Remyelination Is Extensive in a Subset of Multiple Sclerosis Patients","volume":"129","author":"Patrikios","year":"2006","journal-title":"Brain"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1016\/j.febslet.2011.03.048","article-title":"Regulation of Remyelination in Multiple Sclerosis","volume":"585","author":"Hanafy","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e18246","DOI":"10.7554\/eLife.18246","article-title":"Accelerated Remyelination during Inflammatory Demyelination Prevents Axonal Loss and Improves Functional Recovery","volume":"5","author":"Mei","year":"2016","journal-title":"eLife"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41593-023-01558-3","article-title":"Oligodendrocyte\u2013Axon Metabolic Coupling Is Mediated by Extracellular K+ and Maintains Axonal Health","volume":"27","author":"Looser","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature11007","article-title":"Glycolytic Oligodendrocytes Maintain Myelin and Long-Term Axonal Integrity","volume":"485","author":"Supplie","year":"2012","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.neuron.2016.05.016","article-title":"Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism","volume":"91","author":"Saab","year":"2016","journal-title":"Neuron"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"102722","DOI":"10.1016\/j.conb.2023.102722","article-title":"Oligodendrocyte-Derived Transcellular Signaling Regulates Axonal Energy Metabolism","volume":"80","author":"Li","year":"2023","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e36428","DOI":"10.7554\/eLife.36428","article-title":"Oligodendrocyte-Encoded Kir4.1 Function Is Required for Axonal Integrity","volume":"7","author":"Schirmer","year":"2018","journal-title":"eLife"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1038\/s41593-024-01749-6","article-title":"Oligodendroglial Fatty Acid Metabolism as a Central Nervous System Energy Reserve","volume":"27","author":"Asadollahi","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nm.2324","article-title":"A Reversible Form of Axon Damage in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis","volume":"17","author":"Merkler","year":"2011","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.neuron.2018.12.023","article-title":"Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis","volume":"101","author":"Witte","year":"2019","journal-title":"Neuron"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3934\/Neuroscience.2025027","article-title":"Remyelination as a Therapeutic Target in the Treatment of Multiple Sclerosis","volume":"12","author":"Garcha","year":"2025","journal-title":"AIMS Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1212\/WNL.0b013e3181a8260a","article-title":"Remyelination Capacity of the MS Brain Decreases with Disease Chronicity","volume":"72","author":"Goldschmidt","year":"2009","journal-title":"Neurology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1750-3639.2006.00043.x","article-title":"Extensive Cortical Remyelination in Patients with Chronic Multiple Sclerosis","volume":"17","author":"Albert","year":"2007","journal-title":"Brain Pathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1007\/s00415-015-7689-4","article-title":"Can MS Lesion Stages Be Distinguished with MRI? A Postmortem MRI and Histopathology Study","volume":"262","author":"Jonkman","year":"2015","journal-title":"J. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00401-018-1818-y","article-title":"Progressive Multiple Sclerosis Patients Show Substantial Lesion Activity That Correlates with Clinical Disease Severity and Sex: A Retrospective Autopsy Cohort Analysis","volume":"135","author":"Luchetti","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.3390\/brainsci3031282","article-title":"Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination","volume":"3","author":"Podbielska","year":"2013","journal-title":"Brain Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1023\/A:1025747832215","article-title":"The Response of NG2-Expressing Oligodendrocyte Progenitors to Demyelination in MOG-EAE and MS","volume":"31","author":"Reynolds","year":"2002","journal-title":"J. Neurocytol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s00401-013-1112-y","article-title":"Insufficient OPC Migration into Demyelinated Lesions Is a Cause of Poor Remyelination in MS and Mouse Models","volume":"125","author":"Boyd","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1056\/NEJMoa010994","article-title":"Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis","volume":"346","author":"Chang","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1093\/brain\/awq250","article-title":"Demyelination versus Remyelination in Progressive Multiple Sclerosis","volume":"133","author":"Bramow","year":"2010","journal-title":"Brain"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1093\/brain\/awn096","article-title":"Differentiation Block of Oligodendroglial Progenitor Cells as a Cause for Remyelination Failure in Chronic Multiple Sclerosis","volume":"131","author":"Kuhlmann","year":"2008","journal-title":"Brain"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1002\/glia.24068","article-title":"Microglia Contributes to Remyelination in Cerebral but Not Spinal Cord Ischemia","volume":"69","author":"Pavic","year":"2021","journal-title":"Glia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1021\/acs.jproteome.3c00443","article-title":"Lipidomic Analysis Reveals Differences in the Extent of Remyelination in the Brain and Spinal Cord","volume":"23","author":"Kobayashi","year":"2024","journal-title":"J. Proteome Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/jnen\/nlx023","article-title":"Cortical Remyelination Is Heterogeneous in Multiple Sclerosis","volume":"76","author":"Strijbis","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/ana.23693","article-title":"Cortical Remyelination: A New Target for Repair Therapies in Multiple Sclerosis","volume":"72","author":"Chang","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1038\/s41598-018-19934-6","article-title":"Grey Matter OPCs Are Less Mature and Less Sensitive to IFN\u03b3 than White Matter OPCs: Consequences for Remyelination","volume":"8","author":"Lentferink","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1159\/000072270","article-title":"The Cortical Ancestry of Oligodendrocytes: Common Principles and Novel Features","volume":"25","author":"Noble","year":"2003","journal-title":"Dev. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1002\/glia.23607","article-title":"Diversity in the Oligodendrocyte Lineage: Plasticity or Heterogeneity?","volume":"67","author":"Foerster","year":"2019","journal-title":"Glia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.expneurol.2006.05.012","article-title":"Females Remyelinate More Efficiently than Males Following Demyelination in the Aged but Not Young Adult CNS","volume":"202","author":"Li","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Alvarez-Sanchez, N., and Dunn, S.E. (2023). Potential Biological Contributers to the Sex Difference in Multiple Sclerosis Progression. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1175874"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1523\/JNEUROSCI.23-09-03735.2003","article-title":"Netrin-1 Is a Chemorepellent for Oligodendrocyte Precursor Cells in the Embryonic Spinal Cord","volume":"23","author":"Jarjour","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1002\/ana.24201","article-title":"Early Netrin-1 Expression Impairs Central Nervous System Remyelination","volume":"76","author":"Kerninon","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.expneurol.2013.11.012","article-title":"Knockdown of Lingo1b Protein Promotes Myelination and Oligodendrocyte Differentiation in Zebrafish","volume":"251","author":"Yin","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1093\/brain\/awf216","article-title":"Re-expression of PSA-NCAM by Demyelinated Axons: An Inhibitor of Remyelination in Multiple Sclerosis?","volume":"125","author":"Charles","year":"2002","journal-title":"Brain"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7585","DOI":"10.1073\/pnas.100076197","article-title":"Negative Regulation of Central Nervous System Myelination by Polysialylated-Neural Cell Adhesion Molecule","volume":"97","author":"Charles","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.neuroscience.2010.08.070","article-title":"Remyelination after Cuprizone Induced Demyelination Is Accelerated in Mice Deficient in the Polysialic Acid Synthesizing Enzyme St8siaIV","volume":"171","author":"Koutsoudaki","year":"2010","journal-title":"Neuroscience"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1093\/jnen\/nly081","article-title":"Galectin-4, a Negative Regulator of Oligodendrocyte Differentiation, Is Persistently Present in Axons and Microglia\/Macrophages in Multiple Sclerosis Lesions","volume":"77","author":"Stancic","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/glia.22324","article-title":"Galectin-4, a Novel Neuronal Regulator of Myelination","volume":"60","author":"Stancic","year":"2012","journal-title":"Glia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e123434","DOI":"10.1172\/jci.insight.123434","article-title":"Neuronal Activity in Vivo Enhances Functional Myelin Repair","volume":"4","author":"Ortiz","year":"2019","journal-title":"JCI Insight"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41467-017-02719-2","article-title":"Pharmacogenetic Stimulation of Neuronal Activity Increases Myelination in an Axon-Specific Manner","volume":"9","author":"Mitew","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/nn.3469","article-title":"M2 Microglia and Macrophages Drive Oligodendrocyte Differentiation during CNS Remyelination","volume":"16","author":"Miron","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/nn738","article-title":"TNF\u03b1 Promotes Proliferation of Oligodendrocyte Progenitors and Remyelination","volume":"4","author":"Arnett","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e20191390","DOI":"10.1084\/jem.20191390","article-title":"Pro-Inflammatory Activation Following Demyelination Is Required for Myelin Clearance and Oligodendrogenesis","volume":"217","author":"Cunha","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1093\/brain\/awx008","article-title":"Adaptive Human Immunity Drives Remyelination in a Mouse Model of Demyelination","volume":"140","author":"Sanson","year":"2017","journal-title":"Brain"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/jnr.20763","article-title":"Corticosteroids Delay Remyelination of Experimental Demyelination in the Rodent Central Nervous System","volume":"83","author":"Chari","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/j.1365-2826.2011.02140.x","article-title":"Corticosteroids Impair Remyelination in the Corpus Callosum of Cuprizone-Treated Mice","volume":"23","author":"Clarner","year":"2011","journal-title":"J. Neuroendocrinol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/s41586-019-0903-2","article-title":"Altered Human Oligodendrocyte Heterogeneity in Multiple Sclerosis","volume":"566","author":"Agirre","year":"2019","journal-title":"Nature"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1365-2990.1993.tb00424.x","article-title":"Failure of Remyelination in Areas of Demyelination Produced in the Spinal Cord of Old Rats","volume":"19","author":"Gilson","year":"1993","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1016\/j.ajpath.2012.01.018","article-title":"Focal Immune-Mediated White Matter Demyelination Reveals an Age-Associated Increase in Axonal Vulnerability and Decreased Remyelination Efficiency","volume":"180","author":"Hampton","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/nn.2172","article-title":"Age-Dependent Epigenetic Control of Differentiation Inhibitors Is Critical for Remyelination Efficiency","volume":"11","author":"Shen","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/(SICI)1098-1136(199910)28:1<77::AID-GLIA9>3.0.CO;2-F","article-title":"Remyelination Occurs as Extensively but More Slowly in Old Rats Compared to Young Rats Following Gliotoxin-Induced CNS Demyelination","volume":"28","author":"Shields","year":"1999","journal-title":"Glia"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1126\/science.aan4183","article-title":"Defective Cholesterol Clearance Limits Remyelination in the Aged Central Nervous System","volume":"359","author":"Fitzner","year":"2018","journal-title":"Science"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.stem.2019.08.015","article-title":"Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells","volume":"25","author":"Neumann","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s43587-026-01071-9","article-title":"ACSS2 Maintains Oligodendrocyte Progenitor Cell Pool and Is Required for Myelination during Development and Aging","volume":"6","author":"Gao","year":"2026","journal-title":"Nat. Aging"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3581","DOI":"10.1093\/brain\/awv289","article-title":"Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination","volume":"138","author":"Natrajan","year":"2015","journal-title":"Brain"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"9951","DOI":"10.1038\/s41467-025-64906-w","article-title":"Age-Impaired Remyelination Is Associated with Dysregulated Microglial Transitions","volume":"16","author":"Zia","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1038\/s41467-025-57632-w","article-title":"Senescent-like Microglia Limit Remyelination through the Senescence Associated Secretory Phenotype","volume":"16","author":"Gross","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrm3823","article-title":"Cellular Senescence: From Physiology to Pathology","volume":"15","author":"Serrano","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"724","DOI":"10.15252\/embj.201592862","article-title":"Mitochondria Are Required for Pro-Ageing Features of the Senescent Phenotype","volume":"35","author":"Marques","year":"2016","journal-title":"EMBO J."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Kritsilis, M., Rizou, S.V., Koutsoudaki, P.N., Evangelou, K., Gorgoulis, V.G., and Papadopoulos, D. (2018). Ageing, Cellular Senescence and Neurodegenerative Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102937"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/ana.27195","article-title":"Accelerated Cellular Senescence in Progressive Multiple Sclerosis: A Histopathological Study","volume":"97","author":"Papadopoulos","year":"2025","journal-title":"Ann. Neurol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.4161\/15384101.2014.973327","article-title":"Gene Expression Profiling of Replicative and Induced Senescence","volume":"13","author":"Purcell","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"9030","DOI":"10.1073\/pnas.1818348116","article-title":"Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis","volume":"116","author":"Nicaise","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"111366","DOI":"10.1016\/j.mad.2020.111366","article-title":"Cellular Senescence and Failure of Myelin Repair in Multiple Sclerosis","volume":"192","author":"Koutsoudaki","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"e16301","DOI":"10.1111\/jnc.16301","article-title":"Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis","volume":"169","author":"Maupin","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/brain\/104.2.383","article-title":"The Restoration of Conduction by Central Remyelination","volume":"104","author":"Smith","year":"1981","journal-title":"Brain"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/0006-8993(92)90815-Q","article-title":"Conduction Properties of Central Nerve Fibers Remyelinated by Schwann Cells","volume":"574","author":"Felts","year":"1992","journal-title":"Brain Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/ng1095","article-title":"Disruption of Cnp1 Uncouples Oligodendroglial Functions in Axonal Support and Myelination","volume":"33","author":"Goebbels","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1126\/science.280.5369.1610","article-title":"Axonal Swellings and Degeneration in Mice Lacking the Major Proteolipid of Myelin","volume":"280","author":"Griffiths","year":"1998","journal-title":"Science"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1002\/jnr.23923","article-title":"Neuroprotection by Central Nervous System Remyelination: Molecular, Cellular, and Functional Considerations","volume":"94","author":"Verden","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/S0169-328X(02)00188-2","article-title":"Molecular Cloning, Distribution and Functional Analysis of the NAV1.6. Voltage-Gated Sodium Channel from Human Brain","volume":"103","author":"Burbidge","year":"2002","journal-title":"Mol. Brain Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"7272","DOI":"10.1523\/JNEUROSCI.4747-14.2015","article-title":"Myelin Loss and Axonal Ion Channel Adaptations Associated with Gray Matter Neuronal Hyperexcitability","volume":"35","author":"Hamada","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/brain\/awh032","article-title":"Co-localization of Sodium Channel Nav1.6 and the Sodium\u2013Calcium Exchanger at Sites of Axonal Injury in the Spinal Cord in EAE","volume":"127","author":"Craner","year":"2004","journal-title":"Brain"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1093\/brain\/awl057","article-title":"Remyelination of Dorsal Column Axons by Endogenous Schwann Cells Restores the Normal Pattern of Nav1.6 and Kv1.2 at Nodes of Ranvier","volume":"129","author":"Black","year":"2006","journal-title":"Brain"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1093\/brain\/awl144","article-title":"Nodal, Paranodal and Juxtaparanodal Axonal Proteins during Demyelination and Remyelination in Multiple Sclerosis","volume":"129","author":"Coman","year":"2006","journal-title":"Brain"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s004010050873","article-title":"Focal Accumulation of Intra-Axonal Mitochondria in Demyelination of the Cat Optic Nerve","volume":"96","author":"Mutsaers","year":"1998","journal-title":"Acta Neuropathol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1093\/brain\/awr110","article-title":"Increased Mitochondrial Content in Remyelinated Axons: Implications for Multiple Sclerosis","volume":"134","author":"Zambonin","year":"2011","journal-title":"Brain"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1093\/brain\/awn080","article-title":"Remyelination Protects Axons from Demyelination-Associated Axon Degeneration","volume":"131","author":"Irvine","year":"2008","journal-title":"Brain"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0002-9440(10)64537-3","article-title":"Multiple Sclerosis and Chronic Autoimmune Encephalomyelitis: A Comparative Quantitative Study of Axonal Injury in Active, Inactive, and Remyelinated Lesions","volume":"157","author":"Kornek","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1093\/brain\/awf235","article-title":"Acute Axonal Damage in Multiple Sclerosis Is Most Extensive in Early Disease Stages and Decreases over Time","volume":"125","author":"Kuhlmann","year":"2002","journal-title":"Brain"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1093\/brain\/123.2.308","article-title":"Axonal Changes in Chronic Demyelinated Cervical Spinal Cord Plaques","volume":"123","author":"Lovas","year":"2000","journal-title":"Brain"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/ana.24620","article-title":"Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis","volume":"79","author":"Bodini","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"e209604","DOI":"10.1212\/WNL.0000000000209604","article-title":"Quantifying Remyelination Using \u03c7-Separation in White Matter and Cortical Multiple Sclerosis Lesions","volume":"103","author":"Lu","year":"2024","journal-title":"Neurology"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1177\/13524585211008760","article-title":"Current Status of Neuroprotective and Neuroregenerative Strategies in Multiple Sclerosis: A Systematic Review","volume":"28","author":"Allanach","year":"2022","journal-title":"Mult. Scler."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s12264-015-1555-3","article-title":"Clemastine Rescues Behavioral Changes and Enhances Remyelination in the Cuprizone Mouse Model of Demyelination","volume":"31","author":"Li","year":"2015","journal-title":"Neurosci. Bull."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nature12647","article-title":"A Regenerative Approach to the Treatment of Multiple Sclerosis","volume":"502","author":"Deshmukh","year":"2013","journal-title":"Nature"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/nm.3618","article-title":"Micropillar Arrays as a High-Throughput Screening Platform for Therapeutics in Multiple Sclerosis","volume":"20","author":"Mei","year":"2014","journal-title":"Nat. Med."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1523\/JNEUROSCI.3608-15.2016","article-title":"Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice","volume":"36","author":"Liu","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1016\/S0140-6736(17)32346-2","article-title":"Clemastine Fumarate as a Remyelinating Therapy for Multiple Sclerosis (ReBUILD): A Randomised, Controlled, Double-Blind, Crossover Trial","volume":"390","author":"Green","year":"2017","journal-title":"Lancet"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"e183941","DOI":"10.1172\/JCI183941","article-title":"Clemastine Fumarate Accelerates Accumulation of Disability in Progressive Multiple Sclerosis by Enhancing Pyroptosis","volume":"135","author":"Kocot","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s40265-025-02212-x","article-title":"The Road to Remyelination in Multiple Sclerosis: Breakthroughs, Challenges, and Considerations for Future Trial Design","volume":"85","author":"Zuroff","year":"2025","journal-title":"Drugs"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1097\/WNO.0000000000000697","article-title":"Initial Impairment and Recovery of Vision-Related Functioning in Participants With Acute Optic Neuritis From the RENEW Trial of Opicinumab","volume":"39","author":"Petrillo","year":"2019","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S1474-4422(19)30137-1","article-title":"Safety and Efficacy of Opicinumab in Patients with Relapsing Multiple Sclerosis (SYNERGY): A Randomised, Placebo-Controlled, Phase 2 Trial","volume":"18","author":"Cadavid","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S1474-4422(16)30377-5","article-title":"Safety and Efficacy of Opicinumab in Acute Optic Neuritis (RENEW): A Randomised, Placebo-Controlled, Phase 2 Trial","volume":"16","author":"Cadavid","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S1474-4422(21)00179-4","article-title":"Safety and Efficacy of Bexarotene in Patients with Relapsing-Remitting Multiple Sclerosis (CCMR One): A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2a Study","volume":"20","author":"Brown","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s00415-016-8341-7","article-title":"Lesion Remyelinating Activity of GSK239512 versus Placebo in Patients with Relapsing-Remitting Multiple Sclerosis: A Randomised, Single-Blind, Phase II Study","volume":"264","author":"Schwartzbach","year":"2017","journal-title":"J. Neurol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1756286419833574","DOI":"10.1177\/1756286419833574","article-title":"The Monoclonal Antibody GNbAC1: Targeting Human Endogenous Retroviruses in Multiple Sclerosis","volume":"12","author":"Diebold","year":"2019","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"105525","DOI":"10.1016\/j.msard.2024.105525","article-title":"Feasibility Study to Assess Lesion Repair in Relapsing-Remitting Multiple Sclerosis: A Randomized Controlled Pilot Clinical Trial of Domperidone Add-on Treatment","volume":"85","author":"Zhang","year":"2024","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"e2313","DOI":"10.1212\/WNL.0000000000011863","article-title":"Repurposing Domperidone in Secondary Progressive Multiple Sclerosis: A Simon 2-Stage Phase 2 Futility Trial","volume":"96","author":"Koch","year":"2021","journal-title":"Neurology"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"e213951","DOI":"10.1212\/WNL.0000000000213951","article-title":"Effects of Phenytoin on the Retinal Ganglion Cell-Inner Plexiform Layer in Acute Optic Neuritis","volume":"105","author":"Kodali","year":"2025","journal-title":"Neurology"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1093\/brain\/aws284","article-title":"The Neural Androgen Receptor: A Therapeutic Target for Myelin Repair in Chronic Demyelination","volume":"136","author":"Hussain","year":"2013","journal-title":"Brain"},{"key":"ref_170","unstructured":"University Hospital, Strasbourg, France (2025). TOTEM RRMS: TestOsterone TreatmEnt on Neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis, clinicaltrials.gov."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"De Keersmaecker, A.-V., Van Doninck, E., Popescu, V., Willem, L., Cambron, M., Laureys, G., D\u2019 Haeseleer, M., Bjerke, M., Roelant, E., and Lemmerling, M. (2024). A Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination and Neurodegeneration (MACSiMiSE-BRAIN): Study Protocol for a Multi-Center Randomized Placebo Controlled Clinical Trial. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1362629"},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Cunniffe, N.G., Riboni-Verri, G., McMurran, C., Mukherjee, T., Daruwalla, C., Holland, J., Gautam, R., Harding, J., Robertson, N., and Smith, K. (2025, January 24\u201326). Evaluating the Remyelinating Efficacy and Safety of the Combination of Metformin and Clemastine in People with Relapsing Remitting Multiple Sclerosis (CCMR-Two CCMR-Two): A Randomised, Placebo-Controlled, Double-Blind, Phase 2 Clinical Trial. Proceedings of the 41st European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, Barcelona, Spain.","DOI":"10.1186\/s13063-025-09254-2"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.neuro.30.051606.094313","article-title":"Multiple Sclerosis: An Immune or Neurodegenerative Disorder?","volume":"31","author":"Trapp","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Nafe, R., Hattingen, E., Nafe, R., and Hattingen, E. (2026). Pathogenesis of Multiple Sclerosis with Special Consideration of Iron Metabolism, Ferroptosis and Other Forms of Programmed Cell Death. Front. Biosci. (Landmark Ed.), 31.","DOI":"10.31083\/FBL45799"},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Papadopoulos, D., Magliozzi, R., Mitsikostas, D.D., Gorgoulis, V.G., and Nicholas, R.S. (2020). Aging, Cellular Senescence, and Progressive Multiple Sclerosis. Front. Cell Neurosci., 14.","DOI":"10.3389\/fncel.2020.00178"},{"key":"ref_176","unstructured":"Bove, R. (2025). A Phase II Randomized, Double-Blind, Parallel-Group, Placebo Controlled Delayed-Start Trial to Assess the Efficacy, Safety, and Tolerability of Bazedoxifene Acetate (BZA) as a Remyelinating Agent in Patients with Multiple Sclerosis, clinicaltrials.gov."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1002\/acn3.51662","article-title":"Remyelination Varies between and within Lesions in Multiple Sclerosis Following Bexarotene","volume":"9","author":"Brown","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/13524585251396433","article-title":"Safety and Efficacy of Opicinumab in Participants with Relapsing Multiple Sclerosis (AFFINITY Part 1): A Randomized, Controlled, Phase 2 Trial","volume":"32","author":"Calabresi","year":"2026","journal-title":"Mult. Scler."},{"key":"ref_179","unstructured":"University of California, San Francisco (2026). A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Trial to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis, clinicaltrials.gov."},{"key":"ref_180","unstructured":"Centre Hospitalier National d\u2019Ophtalmologie des Quinze-Vingts (2019). Effect of Transorbital Electrical STIMulation of Optic Nerve on Remyelination After an Acute Optic Neuritis, clinicaltrials.gov."},{"key":"ref_181","unstructured":"University of Zurich (2021). Assessing Repetitive Transorbital Alternating Current Stimulation in Acute Autoimmune Inflammatory Optic Neuritis Using the NextWave\u00ae 1.1 System: A Prospective, Randomized, Patient-Blinded, Sham-Controlled Pilot Study, clinicaltrials.gov."},{"key":"ref_182","unstructured":"Clene Nanomedicine (2023). A Phase 2, Randomized, DB-PC, Parallel Group Study for the Treatment of Visual Pathway Deficits In Chronic Optic Neuropathy to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of CNM-Au8 For Remyelination In Multiple Sclerosis, clinicaltrials.gov."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/6\/1183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:06:49Z","timestamp":1781780809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/6\/1183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":182,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["medicina62061183"],"URL":"https:\/\/doi.org\/10.3390\/medicina62061183","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]}}}