{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T13:50:05Z","timestamp":1779889805528,"version":"3.53.1"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,17]],"date-time":"2023-12-17T00:00:00Z","timestamp":1702771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Eye Institute (NEI)","award":["R00EY027013"],"award-info":[{"award-number":["R00EY027013"]}]},{"name":"National Eye Institute (NEI)","award":["R01EY033415"],"award-info":[{"award-number":["R01EY033415"]}]},{"name":"USF TCOP","award":["R00EY027013"],"award-info":[{"award-number":["R00EY027013"]}]},{"name":"USF TCOP","award":["R01EY033415"],"award-info":[{"award-number":["R01EY033415"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO3)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone\u2019s effect on protective gene expression, we performed RT\u2013PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone\u2019s impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE\/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO3 model, daily intraperitoneal injection (i.p.) of buspirone (30 mg\/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1, Cat, Sqstm1, Gstm1, and Sod2 genes in the RPE\/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.<\/jats:p>","DOI":"10.3390\/antiox12122129","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T05:41:35Z","timestamp":1702878095000},"page":"2129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Buspirone Enhances Cell Survival and Preserves Structural Integrity during Oxidative Injury to the Retinal Pigment Epithelium"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9685-2923","authenticated-orcid":false,"given":"Manas R.","family":"Biswal","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, USF Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Paulson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, USF Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riddhi","family":"Vichare","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, USF Taneja College of Pharmacy, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4192-9727","authenticated-orcid":false,"given":"Alfred S.","family":"Lewin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32603, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e7901270","DOI":"10.1155\/2020\/7901270","article-title":"Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models","volume":"2020","author":"Abokyi","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_2","first-page":"359","article-title":"Oxidative Stress Is the Principal Contributor to Inflammasome Activation in Retinal Pigment Epithelium Cells with Defunct Proteasomes and Autophagy","volume":"49","author":"Piippo","year":"2018","journal-title":"CPB"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1096\/fasebj.2.9.2836252","article-title":"Buspirone, a New Approach to the Treatment of Anxiety","volume":"2","author":"Taylor","year":"1988","journal-title":"FASEB J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/j.1875-9114.1988.tb03543.x","article-title":"Buspirone: An Update on a Unique Anxiolytic Agent","volume":"8","author":"Jann","year":"1988","journal-title":"Pharmacotherapy"},{"key":"ref_5","first-page":"e39304","article-title":"Buspirone in Autism Spectrum Disorder: A Systematic Review","volume":"15","author":"Gupta","year":"2023","journal-title":"Cureus"},{"key":"ref_6","first-page":"510285","article-title":"Current Treatment Limitations in Age-Related Macular Degeneration and Future Approaches Based on Cell Therapy and Tissue Engineering","volume":"2014","author":"Sancho","year":"2014","journal-title":"J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"F1119","DOI":"10.1152\/ajprenal.00077.2018","article-title":"5-HT1F Receptor Regulates Mitochondrial Homeostasis and Its Loss Potentiates Acute Kidney Injury and Impairs Renal Recovery","volume":"315","author":"Gibbs","year":"2018","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0165-3806(01)00240-1","article-title":"Astrocyte-Mediated Trophic Support of Developing Serotonin Neurons: Effects of Ethanol, Buspirone, and S100B","volume":"131","author":"Eriksen","year":"2001","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1017\/S1461145702002869","article-title":"Region-Dependent Effects of Flibanserin and Buspirone on Adenylyl Cyclase Activity in the Human Brain","volume":"5","author":"Marazziti","year":"2002","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Thomas Broome, S., and Castorina, A. (2022). The Anxiolytic Drug Buspirone Prevents Rotenone-Induced Toxicity in a Mouse Model of Parkinson\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031845"},{"key":"ref_11","first-page":"582","article-title":"Buspirone along with Melatonin Attenuates Oxidative Damage and Anxiety-like Behavior in a Mouse Model of Immobilization Stress","volume":"12","author":"Kumar","year":"2014","journal-title":"Chin. J. Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kushwah, N., Bora, K., Maurya, M., Pavlovich, M.C., and Chen, J. (2023). Oxidative Stress and Antioxidants in Age-Related Macular Degeneration. Antioxidants, 12.","DOI":"10.3390\/antiox12071379"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0039-6257(00)00140-5","article-title":"The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration","volume":"45","author":"Beatty","year":"2000","journal-title":"Surv. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"595","DOI":"10.3389\/fphys.2017.00595","article-title":"Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and Its Potential Role as a Redox Sensitive Molecular Switch","volume":"8","author":"Ross","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7962393","DOI":"10.1155\/2020\/7962393","article-title":"Tribulus Terrestris Ameliorates Oxidative Stress-Induced ARPE-19 Cell Injury through the PI3K\/Akt-Nrf2 Signaling Pathway","volume":"2020","author":"Yuan","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez-Barrio, C., Del Olmo-Aguado, S., Garc\u00eda-P\u00e9rez, E., de la Fuente, M., Muruzabal, F., Anitua, E., Baamonde-Arbaiza, B., Fern\u00e1ndez-Vega-Cueto, L., Fern\u00e1ndez-Vega, L., and Merayo-Lloves, J. (2020). Antioxidant Role of PRGF on RPE Cells after Blue Light Insult as a Therapy for Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031021"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1161\/HYPERTENSIONAHA.109.139428","article-title":"Glutathione S-Transferase-\u039c1 Regulates Vascular Smooth Muscle Cell Proliferation, Migration, and Oxidative Stress","volume":"54","author":"Yang","year":"2009","journal-title":"Hypertension"},{"key":"ref_18","first-page":"2173","article-title":"Ocular Pathology in Mitochondrial Superoxide Dismutase (Sod2)-Deficient Mice","volume":"42","author":"Sandbach","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3426","DOI":"10.1167\/iovs.05-0344","article-title":"SOD2 Protects against Oxidation-Induced Apoptosis in Mouse Retinal Pigment Epithelium: Implications for Age-Related Macular Degeneration","volume":"46","author":"Kasahara","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1167\/iovs.10-6304","article-title":"Agonists at the Serotonin Receptor (5-HT(1A)) Protect the Retina from Severe Photo-Oxidative Stress","volume":"52","author":"Collier","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.exer.2015.07.022","article-title":"Systemic Treatment with a 5HT1a Agonist Induces Anti-Oxidant Protection and Preserves the Retina from Mitochondrial Oxidative Stress","volume":"140","author":"Biswal","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_22","first-page":"294","article-title":"Repurposing an Orally Available Drug for the Treatment of Geographic Atrophy","volume":"22","author":"Ahmed","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Coyner, A.S., Ryals, R.C., Ku, C.A., Fischer, C.M., Patel, R.C., Datta, S., Yang, P., Wen, Y., Hen, R., and Pennesi, M.E. (2016). Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159776"},{"key":"ref_24","first-page":"443","article-title":"Morphologic and Histopathologic Change of Sodium Iodate-Induced Retinal Degeneration in Adult Rats","volume":"12","author":"Liu","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109728","DOI":"10.1016\/j.exer.2023.109728","article-title":"Regulated Cell Death Pathways in the Sodium Iodate Model: Insights and Implications for AMD","volume":"238","author":"Upadhyay","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.exer.2018.10.009","article-title":"Rapid Differentiation of the Human RPE Cell Line, ARPE-19, Induced by Nicotinamide","volume":"179","author":"Hazim","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/exer.1996.0020","article-title":"ARPE-19, a Human Retinal Pigment Epithelial Cell Line with Differentiated Properties","volume":"62","author":"Dunn","year":"1996","journal-title":"Exp. Eye Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"153375","DOI":"10.1016\/j.phymed.2020.153375","article-title":"Naringenin Protects RPE Cells from NaIO3-Induced Oxidative Damage in Vivo and in Vitro through up-Regulation of SIRT1","volume":"80","author":"Chen","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Juel, H.B., Faber, C., Svendsen, S.G., Vallejo, A.N., and Nissen, M.H. (2013). Inflammatory Cytokines Protect Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Death. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064619"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbrc.2022.07.003","article-title":"Protective Effects of CRTH2 Suppression in Dry Age-Related Macular Degeneration","volume":"624","author":"Xie","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41419-019-2216-7","article-title":"Inhibition of Thyroid Hormone Signaling Protects Retinal Pigment Epithelium and Photoreceptors from Cell Death in a Mouse Model of Age-Related Macular Degeneration","volume":"11","author":"Ma","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bardak, H., U\u011fuz, A.C., Bardak, Y., Rocha-Pimienta, J., Delgado-Ad\u00e1mez, J., and Espino, J. (2023). Selenium Protects ARPE-19 and ACBRI 181 Cells against High Glucose-Induced Oxidative Stress. Molecules, 28.","DOI":"10.3390\/molecules28165961"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1167\/iovs.04-1369","article-title":"Flavonoids Protect Human Retinal Pigment Epithelial Cells from Oxidative-Stress\u2013Induced Death","volume":"47","author":"Hanneken","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"srep43736","DOI":"10.1038\/srep43736","article-title":"Inhibition of Proliferation and Epithelial Mesenchymal Transition in Retinal Pigment Epithelial Cells by Heavy Chain-Hyaluronan\/Pentraxin 3","volume":"7","author":"He","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1007\/s11033-019-04597-x","article-title":"An in Vitro Protocol to Study the Effect of Hyperglycemia on Intracellular Redox Signaling in Human Retinal Pigment Epithelial (ARPE-19) Cells","volume":"46","author":"Gopal","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Biswal, M.R., Justis, B.D., Han, P., Li, H., Gierhart, D., Dorey, C.K., and Lewin, A.S. (2018). Daily Zeaxanthin Supplementation Prevents Atrophy of the Retinal Pigment Epithelium (RPE) in a Mouse Model of Mitochondrial Oxidative Stress. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203816"},{"key":"ref_37","first-page":"515","article-title":"Optical Coherence Tomography Enables Imaging of Tumor Initiation in the TAg-RB Mouse Model of Retinoblastoma","volume":"21","author":"Wenzel","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_38","first-page":"1594","article-title":"Protection of Tight Junction between RPE Cells with Tissue Factor Targeting Peptide","volume":"11","author":"Zou","year":"2018","journal-title":"Int. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00109-017-1506-8","article-title":"Targeting The Tight Junction Protein, Zonula Occludens-1, With The Connexin 43 Mimetic Peptide, \u03b1CT1, Reduces VEGF-Dependent RPE Pathophysiology","volume":"95","author":"Obert","year":"2017","journal-title":"J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Trakkides, T.-O., Sch\u00e4fer, N., Reichenthaler, M., K\u00fchn, K., Brandwijk, R.J.M.G.E., Toonen, E.J.M., Urban, F., Wegener, J., Enzmann, V., and Pauly, D. (2019). Oxidative Stress Increases Endogenous Complement-Dependent Inflammatory and Angiogenic Responses in Retinal Pigment Epithelial Cells Independently of Exogenous Complement Sources. Antioxidants, 8.","DOI":"10.1101\/722470"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5944","DOI":"10.1021\/acs.jafc.7b01929","article-title":"Lutein Activates the Transcription Factor Nrf2 in Human Retinal Pigment Epithelial Cells","volume":"65","author":"Frede","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1167\/iovs.17-23159","article-title":"The Role of ERK1\/2 Activation in Sarpogrelate-Mediated Neuroprotection","volume":"59","author":"Ku","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.1167\/iovs.15-16378","article-title":"Sarpogrelate, a 5-HT2A Receptor Antagonist, Protects the Retina From Light-Induced Retinopathy","volume":"56","author":"Tullis","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0197-0186(96)00022-8","article-title":"5HT1A Receptor Agonist Differentially Increases Cyclic AMP Concentration in Intact and Lesioned Goldfish Retina. In Vitro Inhibition of Outgrowth by Forskolin","volume":"29","author":"Urbina","year":"1996","journal-title":"Neurochem. Int."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/12\/2129\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:40:24Z","timestamp":1760132424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/12\/2129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,17]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["antiox12122129"],"URL":"https:\/\/doi.org\/10.3390\/antiox12122129","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,17]]}}}