{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:44:15Z","timestamp":1793119455122,"version":"4.5.0"},"reference-count":164,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013832","name":"Universitatea de Medicin\u0103, Farmacie, \u0218tiin\u021be \u0219i Tehnologie din T\u00e2rgu Mure\u0219","doi-asserted-by":"publisher","award":["10126\/2\/17.12.2020"],"award-info":[{"award-number":["10126\/2\/17.12.2020"]}],"id":[{"id":"10.13039\/501100013832","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The disruption of blood\u2013brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained \u2018inside-out\u2019 demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB\u2019s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.<\/jats:p>","DOI":"10.3390\/ijms22168370","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T21:45:06Z","timestamp":1628113506000},"page":"8370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":153,"title":["Reviewing the Significance of Blood\u2013Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment"],"prefix":"10.3390","volume":"22","author":[{"given":"Rodica","family":"Balasa","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d, 540136 Targu Mures, Romania"},{"name":"Neurology 1 Clinic, Emergency Clinical County Hospital Mures, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3033-0583","authenticated-orcid":false,"given":"Laura","family":"Barcutean","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d, 540136 Targu Mures, Romania"},{"name":"Neurology 1 Clinic, Emergency Clinical County Hospital Mures, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana","family":"Mosora","sequence":"additional","affiliation":[{"name":"Neurology 1 Clinic, Emergency Clinical County Hospital Mures, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8374-4977","authenticated-orcid":false,"given":"Doina","family":"Manu","sequence":"additional","affiliation":[{"name":"Advanced Research Center Medical and Pharmaceutical, University of Medicine, Pharmacy, Sciences and Technology \u201cGeorge Emil Palade\u201d, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1177\/1352458517694432","article-title":"New insights into the burden and costs of multiple sclerosis in Europe","volume":"23","author":"Kobelt","year":"2017","journal-title":"Mult. 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