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Although elevated intraocular pressure (IOP) is a major risk factor, many patients develop glaucoma with normal IOP, highlighting the need for neuroprotective therapies. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has shown beneficial effects in diabetes-induced retinal neurodegeneration. This study aimed to evaluate whether sitagliptin eye drops, previously effective in diabetes-induced retinal neurodegeneration, could prevent corticosteroid-induced glaucoma. Glaucoma was induced in mice by periocular injection of dexamethasone (DEX) once weekly for five weeks. Sitagliptin or vehicle eye drops were administered from day 14 to 35. Untreated mice served as controls. DEX treatment caused significant loss of RGC bodies and optic nerve axons compared to controls, which was prevented by sitagliptin eye drops (p &lt; 0.001), without affecting IOP. Sitagliptin also inhibited DEX-induced activation of macroglia and microglia and prevented oligodendrocyte loss. Furthermore, it suppressed overexpression of galectin-3 and gamma-synuclein in the optic nerve head (ONH) (p &lt; 0.001), key mediators of inflammation and apoptosis. Sitagliptin eye drops exert a potent neuroprotective effect against corticosteroid-induced glaucoma, supporting their potential as a novel therapeutic strategy for glaucoma.<\/jats:p>","DOI":"10.3390\/ijms27010048","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T16:19:26Z","timestamp":1766420366000},"page":"48","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Topical Administration of Sitagliptin Prevents Retinal Neurodegeneration in a Model of Glaucoma Induced by Dexamethasone"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0669-4958","authenticated-orcid":false,"given":"Patricia","family":"Bogdanov","sequence":"first","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-5478","authenticated-orcid":false,"given":"Anna","family":"Duarri","sequence":"additional","affiliation":[{"name":"Ophthalmology Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8113-8594","authenticated-orcid":false,"given":"David","family":"Sabater","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Canz","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-3309","authenticated-orcid":false,"given":"Helena","family":"Isla-Magran\u00e9","sequence":"additional","affiliation":[{"name":"Ophthalmology Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6443-7576","authenticated-orcid":false,"given":"Hugo","family":"Ramos","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-6313","authenticated-orcid":false,"given":"Anna","family":"De\u00e0s-Just","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-3096","authenticated-orcid":false,"given":"Rafael","family":"Sim\u00f3","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3109-1721","authenticated-orcid":false,"given":"Cristina","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","first-page":"e11686","article-title":"Epidemiology of Glaucoma: The Past, Present, and Predictions for the 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