{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:54:37Z","timestamp":1790258077122,"version":"4.1.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Optic neuritis (ON) is often an early sign of multiple sclerosis (MS), and recent studies show a link between HIF-1 pathway activation and inflammation. This study aimed to determine if inhibition of the HIF-1 pathway using the HIF-1a antagonist acriflavine (ACF) can reduce clinical progression and rescue the ocular phenotype in an experimental autoimmune encephalomyelitis (EAE) ON model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>EAE-related ON was induced in 60 female C57BL\/6J mice by immunization with MOG33-55, and 20 EAE mice received daily systemic injections of ACF at 5 mg\/kg. Changes in the visual function and structure of ACF-treated EAE mice were compared to those of placebo-injected EAE mice and na\u00efve control mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ACF treatment improved motor\u2013sensory impairment along with preserving visual acuity and optic nerve function. Analysis of retinal ganglion cell complex alsoshowed preserved thickness correlating with increased survival of retinal ganglion cells and their axons. Optic nerve cell infiltration and magnitude of demyelination were decreased in ACF-treated EAE mice. Subsequent in vitro studies revealed improvements not only attributed to the inhibition of HIF-1 butalso to previously unappreciated interaction with the eIF2a\/ATF4 axis in the unfolded protein response pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study suggests that ACF treatment is effective in an animal model of MS via its pleiotropic effects on the inhibition of HIF-1 and UPR signaling, and it may be a viable approach to promote rehabilitation in MS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1271118","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T06:17:25Z","timestamp":1698214645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Acriflavine, a HIF-1 inhibitor, preserves vision in an experimental autoimmune encephalomyelitis model of optic neuritis"],"prefix":"10.3389","volume":"14","author":[{"given":"Jeffrey J.","family":"Anders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin W.","family":"Elwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy H.","family":"Kardon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver W.","family":"Gramlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","article-title":"Multiple sclerosis","volume":"4","author":"Filippi","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/cshperspect.a028936","article-title":"Multiple sclerosis pathology","volume":"8","author":"Lassmann","year":"2018","journal-title":"Cold Spring Harbor Perspect Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1177\/1352458518791683","article-title":"Multiple sclerosis disease progression: Contributions from a hypoxia-inflammation cycle","volume":"25","author":"Yang","year":"2019","journal-title":"Multiple sclerosis (Houndmills Basingstoke England)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(02)00421-5","article-title":"Hypoxia-like tissue injury as a component of multiple sclerosis lesions","volume":"206","author":"Lassmann","year":"2003","journal-title":"J neurological Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa427","article-title":"Hypoxia in multiple sclerosis; is it the chicken or the egg","volume":"144","author":"Halder","year":"2021","journal-title":"Brain J Neurol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1042\/CS20170981","article-title":"Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis","volume":"131","author":"Martinez Sosa","year":"2017","journal-title":"Clin Sci (Lond)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s40478-020-00903-y","article-title":"Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis","volume":"8","author":"Rodriguez-Lorenzo","year":"2020","journal-title":"Acta neuropathologica Commun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms24043073","article-title":"Relationship between hypoxic and immune pathways activation in the progression of neuroinflammation: role of HIF-1alpha and th17 cells","volume":"24","author":"Arias","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00204.2015","article-title":"Hypoxia-inducible factors in T lymphocyte differentiation and function. 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