{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:17:25Z","timestamp":1790705845849,"version":"4.1.0"},"reference-count":77,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["1560\/1561"],"award-info":[{"award-number":["1560\/1561"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Defence, UK","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"The Drummond Foundation, UK","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"Sir Ian Fraser Foundation, Blind Veterans, UK","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by \u03b2III-tubulin+ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)+ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS+ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg\/\u00b5L was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site.<\/jats:p>","DOI":"10.3390\/cells8121517","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T10:57:27Z","timestamp":1574765847000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6202-1347","authenticated-orcid":false,"given":"Chloe N.","family":"Thomas","sequence":"first","affiliation":[{"name":"Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"},{"name":"School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6267-6442","authenticated-orcid":false,"given":"Zubair","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6142-3280","authenticated-orcid":false,"given":"Richard J.","family":"Blanch","sequence":"additional","affiliation":[{"name":"Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"},{"name":"Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham B15 2TT, UK"},{"name":"Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/eye.2010.190","article-title":"Ophthalmic injuries in British Armed Forces in Iraq and Afghanistan","volume":"25","author":"Blanch","year":"2011","journal-title":"Eye"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1016\/S0161-6420(00)00390-0","article-title":"The prevalence and 5-year incidence of ocular trauma\u2014The Beaver Dam Eye Study","volume":"107","author":"Wong","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/S0161-6420(99)00707-1","article-title":"The treatment of traumatic optic neuropathy: The International Optic Nerve Trauma Study","volume":"106","author":"Levin","year":"1999","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1097\/ICU.0000000000000198","article-title":"Is there treatment for traumatic optic neuropathy?","volume":"26","author":"Chaon","year":"2015","journal-title":"Curr. 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