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Due to the growing evidence regarding the key role of neurodegeneration in the earliest stages of the disease and the underlying pathophysiological mechanisms, the relevance of evaluating the potential efficacy of neuroprotective therapies is emphasized. More specifically, the review addresses the current state of a promising neuroprotective approach based on the inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) using specific inhibitors administered via eyedrops, which allow direct retinal action on the neurovascular unit. The review discusses the main preclinical findings of a therapeutic strategy based on one DPP-4 inhibitor, sitagliptin, against early DRD in different experimental animal models and in vitro studies. In summary, sitagliptin eyedrops exhibit neuroprotective, anti-inflammatory, and antioxidant properties while reducing glial activation, hyperpermeability of the blood\u2013retinal barrier, and the formation of acellular capillaries, leading to a functional improvement of the diabetic retina. However, as sitagliptin efficacy has only been evaluated at the preclinical level, clinical studies are needed to validate the translational applicability and long-term efficacy of topical administration not only of sitagliptin but also of other DPP-4 inhibitors for treating retinal diseases in which neurodegeneration plays a pathogenic role.<\/jats:p>","DOI":"10.3390\/ijms27104361","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:27:56Z","timestamp":1778776076000},"page":"4361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Eyedrop Administration of DPP-4 Inhibitors: A New Strategy for Treating Early Stages of Diabetic Retinal Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6443-7576","authenticated-orcid":false,"given":"Hugo","family":"Ramos","sequence":"first","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-652X","authenticated-orcid":false,"given":"Olga","family":"Sim\u00f3-Servat","sequence":"additional","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 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 (VHIR), 08035 Barcelona, Spain"},{"name":"Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain"},{"name":"Department of Medicine, Autonomous University of Barcelona, 08193 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 (VHIR), 08035 Barcelona, Spain"},{"name":"Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain"},{"name":"Department of Medicine, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Seo, H., Park, S.-J., and Song, M. 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