{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:23:53Z","timestamp":1791822233023,"version":"4.3.4"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kakenhi Scientific Research (C) of the Japan Society for the Promotion of Science","award":["17K11449"],"award-info":[{"award-number":["17K11449"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to verify whether dimethyl fumarate (DMF) promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush (ONC) accompanied by activation of the NF-E2-related factor 2 (Nrf2)\/heme oxygenase-1 (HO-1) pathway. We examined changes in the densities of tubulin \u03b23 (TUBB3)-positive RGCs and the amplitudes of the positive scotopic threshold response (pSTR), reflecting the functional activity of RGCs, recorded on an electroretinogram, with daily administration of DMF, on day 7 after ONC. Furthermore, immunohistochemical and immunoblotting analyses were performed to study the activation of the Nrf2\/HO-1 pathway using retinas treated with daily administration of DMF. Daily administration of DMF increasedthe density of TUBB3-positive RGCs in a dose-dependent fashion and significantly increased the amplitude of the pSTR. Immunohistochemical analysis showed that DMF administration increased the immunoreactivity for Nrf2 and HO-1, a potent antioxidant enzyme, in RGCs immunolabeled with RNA-binding protein with multiple splicing (RBPMS). Immunoblotting analysis revealed an increase in the nuclear expression of Nrf2 and marked upregulation of HO-1 after DMF administration. These results suggest that DMF has survival-promoting effects in RGC after ONC, possibly via the Nrf2\/HO-1 pathway.<\/jats:p>","DOI":"10.3390\/ijms22010297","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T09:35:23Z","timestamp":1609320923000},"page":"297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dimethyl Fumarate Promotes the Survival of Retinal Ganglion Cells after Optic Nerve Injury, Possibly through the Nrf2\/HO-1 Pathway"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1991-3232","authenticated-orcid":false,"given":"Sotaro","family":"Mori","sequence":"first","affiliation":[{"name":"Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-8435","authenticated-orcid":false,"given":"Takuji","family":"Kurimoto","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7523-9732","authenticated-orcid":false,"given":"Hidetaka","family":"Maeda","sequence":"additional","affiliation":[{"name":"Maeda Eye Clinic, 1-1-1 Uchihonmachi, Chuo-ku, Osaka 540-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-4302","authenticated-orcid":false,"given":"Makoto","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,30]]},"reference":[{"key":"ref_1","first-page":"278","article-title":"Utilization of dimethyl fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases","volume":"7","author":"Maghazachi","year":"2016","journal-title":"Front Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2147\/TCRM.S85099","article-title":"Dimethyl fumarate in the management of multiple sclerosis: Appropriate patient selection and special considerations","volume":"12","author":"Prosperini","year":"2016","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1089\/ars.2010.3222","article-title":"Discovery of the negative regulator of Nrf2, Keap1: A historical overview","volume":"13","author":"Itoh","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3164\/jcbn.14-134","article-title":"Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria","volume":"56","author":"Itoh","year":"2015","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1172\/JCI72151","article-title":"Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate\u2019s protective effect in EAE","volume":"124","author":"Chen","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00401-015-1422-3","article-title":"Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS","volume":"130","author":"Parodi","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s12975-016-0496-0","article-title":"Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice","volume":"7","author":"Yao","year":"2016","journal-title":"Transl. Stroke Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12974-016-0559-x","article-title":"Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2\/hemoxygenase-1 pathway by altering the balance of M1\/M2 macrophages","volume":"13","author":"Han","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1073\/pnas.1603907113","article-title":"Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2","volume":"113","author":"Pekarek","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3109\/08820139.2011.569626","article-title":"Cytokine secretion pattern in treatment of lymphocytes of multiple sclerosis patients with fumaric acid esters","volume":"40","author":"Zoghi","year":"2011","journal-title":"Immunol. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1002\/eji.1830260916","article-title":"Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate","volume":"26","author":"Bezemer","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1703810","DOI":"10.1155\/2017\/1703810","article-title":"Involvement of Nrf2 in Ocular Diseases","volume":"2017","author":"Batliwala","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/jnr.24543","article-title":"Connecting endoplasmic reticulum and oxidative stress to retinal degeneration, TBI, and traumatic optic neuropathy","volume":"98","author":"Cansler","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1111\/jnc.12325","article-title":"Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death","volume":"127","author":"Himori","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.brainres.2012.12.041","article-title":"Protective effect of lipoic acid against oxidative stress is mediated by Keap1\/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cellline","volume":"1499","author":"Koriyama","year":"2013","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.omtm.2017.04.003","article-title":"Spatially and temporally regulated NRF2 gene therapy using mcp-1 promoter in retinal ganglion cell injury. Molecular therapy","volume":"5","author":"Fujita","year":"2017","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/jnc.14029","article-title":"RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Muller glia cells","volume":"141","author":"Inoue","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1167\/iovs.18-24398","article-title":"Monomethyl fumarate protects the retina from light-induced retinopathy","volume":"60","author":"Jiang","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12974-017-0982-7","article-title":"Microglial dynamics after axotomy-induced retinal ganglion cell death","volume":"14","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1002\/jnr.10713","article-title":"Characterization of activated retinal microglia following optic axotomy","volume":"73","author":"Zhang","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.neuroscience.2005.04.011","article-title":"Effects of minocycline and tetracycline on retinal ganglion cell survival after axotomy","volume":"13","author":"Baptiste","year":"2005","journal-title":"Neuroscience"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s00417-010-1608-2","article-title":"Similarities and differences between primary and secondary degeneration of the optic nerve and the effect of minocycline","volume":"249","author":"Spierer","year":"2011","journal-title":"Graefe Arch. Clin. Exp. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1001\/archopht.124.4.520","article-title":"Minocycline delays death of retinal ganglion cells in experimental glaucoma and after optic nerve transection","volume":"124","author":"Melamed","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14816","DOI":"10.1523\/JNEUROSCI.5511-12.2013","article-title":"Neutrophils express oncomodulin and promote optic nerve regeneration","volume":"33","author":"Kurimoto","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1167\/iovs.14-13895","article-title":"Monitoring retinal morphologic and functional changes in mice following optic nerve crush","volume":"55","author":"Liu","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1007\/s12035-020-02030-0","article-title":"Aqp9 gene deletion enhances retinal ganglion cell (RGC) death and dysfunction induced by optic nerve rush: Evidence that aquaporin 9 acts as an astrocyte-to-neuron lactate shuttle in concert with monocarboxylate transporters to support RGC function and survival","volume":"57","author":"Mori","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15654","DOI":"10.1523\/JNEUROSCI.4340-10.2010","article-title":"Long-distance axon regeneration in the mature optic nerve: Contributions of oncomodulin, cAMP, and pten gene deletion","volume":"30","author":"Kurimoto","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ydbio.2008.01.015","article-title":"Near complete loss of retinal ganglion cells in the math5\/brn3b double knockout elicits severe reductions of other cell types during retinal development","volume":"316","author":"Moshiri","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1471-4159.2010.06903.x","article-title":"Long-acting genipin derivative protects retinal ganglion cells from oxidative stress models in vitro and in vivo through the Nrf2\/antioxidant response element signaling pathway","volume":"115","author":"Koriyama","year":"2010","journal-title":"J. Neurochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/297\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:49Z","timestamp":1760179669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,30]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010297"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010297","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,30]]}}}