{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:00:54Z","timestamp":1792101654351,"version":"4.4.0"},"reference-count":99,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004429","name":"the University of Crete","doi-asserted-by":"publisher","award":["ELKE KA 10752"],"award-info":[{"award-number":["ELKE KA 10752"]}],"id":[{"id":"10.13039\/501100004429","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004429","name":"the University of Crete","doi-asserted-by":"publisher","award":["ELKE KA 10879"],"award-info":[{"award-number":["ELKE KA 10879"]}],"id":[{"id":"10.13039\/501100004429","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Christina Spyraki","award":["ELKE KA 10752"],"award-info":[{"award-number":["ELKE KA 10752"]}]},{"name":"the Christina Spyraki","award":["ELKE KA 10879"],"award-info":[{"award-number":["ELKE KA 10879"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role of NOX2 and the novel NOX2 inhibitor, GLX7013170, in two models of a) retinal AMPA excitotoxicity [AMPA+GLX7013170 (10\u22124 M, intravitreally)] and b) early-stage DR paradigm (ESDR), GLX7013170: 14-day therapeutic treatment (topically, 20 \u03bcL\/eye, 10 mg\/mL (300 \u00d7 10\u22124 M), once daily) post-streptozotocin (STZ)-induced DR. Immunohistochemical studies for neuronal markers, nitrotyrosine, micro\/macroglia, and real-time PCR, Western blot, and glutamate colorimetric assays were conducted. Diabetes increased NOX2 expression in the retina. NOX2 inhibition limited the loss of NOS-positive amacrine cells and the overactivation of micro\/macroglia in both models. In the diabetic retina, GLX7013170 had no effect on retinal ganglion cell axons, but reduced oxidative damage, increased Bcl-2, reduced glutamate levels, and partially restored excitatory amino acid transporter (EAAT1) expression. These results suggest that NOX2 in diabetes is part of the triad, oxidative stress, NOX, and glutamate excitotoxicity, key players in the induction of DR. GLX7013170 is efficacious as a neuroprotective\/anti-inflammatory agent and a potential therapeutic in retinal diseases, including ESDR.<\/jats:p>","DOI":"10.3390\/ph17030393","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T04:36:31Z","timestamp":1710822991000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina"],"prefix":"10.3390","volume":"17","author":[{"given":"Stavroula","family":"Dionysopoulou","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Wikstrom","sequence":"additional","affiliation":[{"name":"Glucox Biotech AB, S-17997 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Walum","sequence":"additional","affiliation":[{"name":"Glucox Biotech AB, S-17997 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spiros","family":"Georgakis","sequence":"additional","affiliation":[{"name":"Laboratory of Rheumatology, Autoimmunity and Inflammation, School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriaki","family":"Thermos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0026-0495(00)80077-3","article-title":"What Is Oxidative Stress?","volume":"49","author":"Betteridge","year":"2000","journal-title":"Metabolism"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8416763","DOI":"10.1155\/2017\/8416763","article-title":"Oxidative Stress: Harms and Benefits for Human Health","volume":"2017","author":"Pizzino","year":"2017","journal-title":"Oxid. 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