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To evaluate the effects and understand the action mechanism of NaV blockers and MAO-B inhibitors (rasagiline, safinamide, flecainide and phenytoin) in neurological conditions, various techniques were used, including optical coherence tomography (OCT), optomotor response measurement (OMR), flow cytometry, histological evaluations, Evans blue assay, blood\u2013brain barrier (BBB) permeability assay, western blot, proliferations assay, and gene expression analyses. The study found that the primary therapeutic effect comes from inhibiting the NaV 1.5 sodium channel, not MAO-B inhibition. Flecainide, a NaV 1.5 channel blocker, significantly reduced EAE disability scores, mitigated neurodegeneration, preserved visual function, and restricted immune cell migration into the CNS. Importantly, blocking the NaV 1.5 channel had an effect on the BBB, limiting lymphocyte entry into the CNS. This research highlights sodium channel blockers\u2019 potential in treating EAE. The findings demonstrate induced neuroprotection and reduced disease progression, suggesting a novel therapeutic approach. 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Mustafa Sindi is funded by a DFG grant to Philipp Albrecht, number AL 1769\/6-1. Apart from this, the authors declare that they have no additional conflict of interest related to the work presented. The following financial disclosures are unrelated to the work: SGM received honoraria for lecturing and travel expenses for34attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kr\u00f6ner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. MD received speaker honoraria from Merck and Novartis. PA received compensation for serving on Scientific Advisory Boards for Ipsen, Novartis, Biogen; he received speaker honoraria and travel support from Novartis, Teva, Biogen, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB and Glaxo Smith Kline; he received research support from Novartis, Biogen, Teva, Merz Pharmaceuticals, Ipsen, Bristol-Myers Squibb and Roche. The other authors report no disclosures. TR reports grants from German Ministry of Education, Science, Research and Technology, during the conduct of the study; grants and personal fees from Sanofi-Genzyme; personal fees from Biogen; personal fees and nonfinancial support from Merck Serono; personal fees from Roche, Teva, Alexion, Argenx, UCB, and BMS outside the submitted work. Author Philipp Albrecht is employed by Maria Hilf Clinics GmbH, M\u00f6nchengladbach. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments in this study were conducted in strict compliance with the ethical guidelines and regulations of the State Office for Nature, Environment and Consumer Protection of North Rhine-Westphalia, Germany \u201cLandesamt f\u00fcr Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, Deutschland\u201d. The study protocol was reviewed and approved under the approval number Az. 81-02.04.2019.A063. We confirm that all experiments were performed in accordance with relevant guidelines and regulations and are reported following the ARRIVE guidelines (PLoS Biol 8(6), e1000412, 2010). The mice used in this study, as described in \u201cAnimals, animal models, treatment\u201d section of this manuscript, included C57BL\/6J mice obtained from Janvier Labs and NOD\/ShiLtJ mice bred in the animal facility at the University of D\u00fcsseldorf (ZETT). Both strains had ad libitum access to chow and drinking water, and measures were taken to minimize suffering. Anesthesia and euthanasia were administered in accordance with AVMA guidelines to ensure humane treatment. Statistical analyses appropriate for each outcome were conducted to assess the results. No client-owned animals were involved in this study; therefore, informed consent from owners was not required.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"31032"}}