{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:54:13Z","timestamp":1790553253259,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"INSERM, INSERM Transfert, Agence National de la Recherche","doi-asserted-by":"publisher","award":["ANR-21-CE18-0018"],"award-info":[{"award-number":["ANR-21-CE18-0018"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"INSERM, INSERM Transfert, Agence National de la Recherche","doi-asserted-by":"publisher","award":["101080611"],"award-info":[{"award-number":["101080611"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EU Framework Horizon Europe Program","award":["ANR-21-CE18-0018"],"award-info":[{"award-number":["ANR-21-CE18-0018"]}]},{"name":"EU Framework Horizon Europe Program","award":["101080611"],"award-info":[{"award-number":["101080611"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Abnormal corneal wound healing can compromise corneal transparency and lead to visual impairment. Mineralocorticoid receptor antagonists (MRA) are promising candidates to promote corneal remodeling with anti-inflammatory properties and lack gluococorticoids-associated side effects. In this preclinical study, a new polymer-free hydroxypropyl-gamma-cyclodextrin-based eyedrop containing 0.1% spironolactone (SPL), a potent but non-water-soluble MRA, was investigated for its ocular surface tolerance and efficacy in a rat model of corneal wound healing. SPL eyedrops were stable for up to 9 months at 4 \u00b0C. The formulation was well-tolerated since no morphological changes or inflammatory reactions were observed in the rat cornea after multiple daily instillations over 7 days. SPL eyedrops accelerated rat corneal wound healing, reduced corneal edema and inflammation, enhanced epithelial integrity, and improved nerve regeneration, suggesting restoration of corneal homeostasis, while potassium canrenoate, an active and soluble metabolite of SPL, had no effect. SPL eyedrops could benefit patients with impaired corneal wound healing, including that secondary to glucocorticoid therapy. Repurposing known drugs with known excipients will expedite translation to the clinic.<\/jats:p>","DOI":"10.3390\/ph16101446","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T03:07:47Z","timestamp":1697080067000},"page":"1446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Spironolactone Eyedrop Favors Restoration of Corneal Integrity after Wound Healing in the Rat"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9906-0610","authenticated-orcid":false,"given":"Daniela","family":"Rodrigues-Braz","sequence":"first","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"G\u00e9liz\u00e9","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Clarin","sequence":"additional","affiliation":[{"name":"Excelvision, Fareva, 07100 Annonay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Chatagnon","sequence":"additional","affiliation":[{"name":"Excelvision, Fareva, 07100 Annonay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youcef","family":"Benzine","sequence":"additional","affiliation":[{"name":"Valdepharm, Fareva, 27100 Val-de-Reuil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Rampignon","sequence":"additional","affiliation":[{"name":"Valdepharm, Fareva, 27100 Val-de-Reuil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7687-0999","authenticated-orcid":false,"given":"Agathe","family":"Thouvenin","sequence":"additional","affiliation":[{"name":"CNRS, Inserm, UTCBS, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"},{"name":"D\u00e9partement Recherche et D\u00e9veloppement Pharmaceutique, Agence G\u00e9n\u00e9rale des Equipements et Produits de Sant\u00e9 (AGEPS), AP-HP, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Bourges","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"},{"name":"Ophtalmopole, AP-HP, Cochin Hospital, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-9513","authenticated-orcid":false,"given":"Francine","family":"Behar-Cohen","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"},{"name":"Ophtalmopole, AP-HP, Cochin Hospital, 75014 Paris, France"},{"name":"H\u00f4pital Foch, Service D\u2019ophtalmologie, 92150 Suresnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5418-7275","authenticated-orcid":false,"given":"Min","family":"Zhao","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Inserm, Universit\u00e9 Paris Cit\u00e9, Sorbonne Universit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.jcrs.2010.12.037","article-title":"Anatomy and Physiology of the Cornea","volume":"37","author":"DelMonte","year":"2011","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/aos.13844","article-title":"Role of Corneal Nerves in Ocular Surface Homeostasis and Disease","volume":"97","author":"Labetoulle","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101090","DOI":"10.1016\/j.preteyeres.2022.101090","article-title":"Corneal Stromal Repair and Regeneration","volume":"91","author":"Mohan","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1097\/ICU.0000000000000861","article-title":"Therapy for Contact Lens-Related Ulcers","volume":"33","author":"Jeang","year":"2022","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1097\/01.ico.0000151544.23360.17","article-title":"Wound Healing in the Cornea: A Review of Refractive Surgery Complications and New Prospects for Therapy","volume":"24","author":"Netto","year":"2005","journal-title":"Cornea"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1080\/07853890.2022.2045035","article-title":"Neurotrophic Keratopathy: Current Challenges and Future Prospects","volume":"54","author":"NaPier","year":"2022","journal-title":"Ann. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.survophthal.2021.02.013","article-title":"Peripheral Ulcerative Keratitis","volume":"66","author":"Gupta","year":"2021","journal-title":"Surv. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"db210099","DOI":"10.2337\/db21-0099","article-title":"Mineralocorticoid Receptor Pathway and Its Antagonism in a Model of Diabetic Retinopathy","volume":"70","author":"Zhao","year":"2021","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Canonica, J., Zhao, M., Favez, T., Geliz\u00e9, E., Jonet, L., Kowalczuk, L., Guegan, J., Le Menuet, D., Viengchareun, S., and Lomb\u00e8s, M. (2021). Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179618"},{"key":"ref_10","first-page":"305","article-title":"Endogenous Cortisol and TGF-Beta in Human Aqueous Humor Contribute to Ocular Immune Privilege by Regulating Dendritic Cell Function","volume":"186","author":"Denniston","year":"2011","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.17116\/oftalma2017133239-44","article-title":"Cortisol levels in plasma and aqueous humour of patients with steroid induced and other glaucomas","volume":"133","author":"Kasimov","year":"2017","journal-title":"Vestn. Oftalmol."},{"key":"ref_12","first-page":"3711","article-title":"The Presence of Biologically Significant Concentrations of Glucocorticoids but Little or No Cortisol Binding Globulin within Aqueous Humor: Relevance to Immune Privilege in the Anterior Chamber of the Eye","volume":"35","author":"Knisely","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Susarla, R., Liu, L., Walker, E.A., Bujalska, I.J., Alsalem, J., Williams, G.P., Sreekantam, S., Taylor, A.E., Tallouzi, M., and Southworth, H.S. (2014). Cortisol Biosynthesis in the Human Ocular Surface Innate Immune Response. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094913"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1089\/jop.2021.0040","article-title":"Corticosteroids in the Management of Infectious Keratitis: A Concise Review","volume":"37","author":"Sharma","year":"2021","journal-title":"J. Ocul. Pharmacol. Ther. Off. J. Assoc. Ocul. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.exer.2016.08.020","article-title":"Glucocorticoid Action in Human Corneal Epithelial Cells Establishes Roles for Corticosteroids in Wound Healing and Barrier Function of the Eye","volume":"152","author":"Kadmiel","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1159\/000127166","article-title":"Immunochemical Demonstration of the Mineralocorticoid Receptor in Ocular Tissues","volume":"65","author":"Mirshahi","year":"1997","journal-title":"Neuroendocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1124\/pr.115.011106","article-title":"Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology","volume":"68","author":"Jaisser","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1016\/j.jid.2016.05.101","article-title":"Re-Epithelialization of Pathological Cutaneous Wounds Is Improved by Local Mineralocorticoid Receptor Antagonism","volume":"136","author":"Nguyen","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1021\/acs.molpharmaceut.7b01028","article-title":"Topical Administration of Spironolactone-Loaded Nanomicelles Prevents Glucocorticoid-Induced Delayed Corneal Wound Healing in Rabbits","volume":"15","author":"Dahmana","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jid.2019.04.030","article-title":"Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade","volume":"140","author":"Nguyen","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41467-018-08125-6","article-title":"Mineralocorticoid Receptor Antagonism Limits Experimental Choroidal Neovascularization and Structural Changes Associated with Neovascular Age-Related Macular Degeneration","volume":"10","author":"Zhao","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/08820530902801478","article-title":"Limbal Stem Cell Deficiency and Corneal Neovascularization","volume":"24","author":"Lim","year":"2009","journal-title":"Semin. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e000779","DOI":"10.1136\/bmjdrc-2019-000779","article-title":"Experimental Modeling of Cornea Wound Healing in Diabetes: Clinical Applications and Beyond","volume":"7","author":"Bu","year":"2019","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/bs.pmbts.2015.05.002","article-title":"Corneal Epithelial Wound Healing","volume":"134","author":"Liu","year":"2015","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.jconrel.2017.09.029","article-title":"Tolerance of High and Low Amounts of PLGA Microspheres Loaded with Mineralocorticoid Receptor Antagonist in Retinal Target Site","volume":"266","author":"Zhao","year":"2017","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, Y., and Wang, C. (2022). Novel Eye Drop Delivery Systems: Advance on Formulation Design Strategies Targeting Anterior and Posterior Segments of the Eye. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061150"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2020.06.016","article-title":"Optimizing Ophthalmic Delivery of a Poorly Water Soluble Drug from an Aqueous in Situ Gelling System","volume":"154","author":"Senjoti","year":"2020","journal-title":"Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahrenstechnik EV"},{"key":"ref_28","first-page":"203","article-title":"New Prostaglandin Analog Formulation for Glaucoma Treatment Containing Cyclodextrins for Improved Stability, Solubility and Ocular Tolerance","volume":"95","author":"Guinchard","year":"2015","journal-title":"Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahrenstechnik EV"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.exer.2014.02.013","article-title":"TGF\u03b2 and PDGF-B Signaling Blockade Inhibits Myofibroblast Development from Both Bone Marrow-Derived and Keratocyte-Derived Precursor Cells in Vivo","volume":"121","author":"Singh","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.exer.2014.09.012","article-title":"The Corneal Fibrosis Response to Epithelial-Stromal Injury","volume":"142","author":"Torricelli","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000471918","article-title":"Eplerenone Prevents Atrial Fibrosis via the TGF-\u03b2 Signaling Pathway","volume":"138","author":"Du","year":"2017","journal-title":"Cardiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.2147\/DDDT.S100095","article-title":"Spirolactone Provides Protection from Renal Fibrosis by Inhibiting the Endothelial-Mesenchymal Transition in Isoprenaline-Induced Heart Failure in Rats","volume":"10","author":"Zhou","year":"2016","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1159\/000374063","article-title":"Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway","volume":"36","author":"Chen","year":"2015","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16802","DOI":"10.1038\/s41598-017-17103-9","article-title":"The Role of Oxidative Stress in the Crosstalk between Leptin and Mineralocorticoid Receptor in the Cardiac Fibrosis Associated with Obesity","volume":"7","author":"Miana","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1111\/bph.15932","article-title":"The Myeloid Mineralocorticoid Receptor Regulates Dermal Angiogenesis and Inflammation in Glucocorticoid-Induced Impaired Wound Healing","volume":"179","author":"Nguyen","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101105","DOI":"10.1016\/j.preteyeres.2022.101105","article-title":"Neuroimmune Crosstalk in the Cornea: The Role of Immune Cells in Corneal Nerve Maintenance during Homeostasis and Inflammation","volume":"91","author":"Wu","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3109\/10799893.2015.1132238","article-title":"Expression of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Peripheral Nerve Repair","volume":"36","author":"Aghanasir","year":"2016","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100762","DOI":"10.1016\/j.preteyeres.2019.05.003","article-title":"Corneal Nerves in Health and Disease","volume":"73","author":"Dhillon","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1167\/iovs.64.2.20","article-title":"Topical Decorin Reduces Corneal Inflammation and Imparts Neuroprotection in a Mouse Model of Benzalkonium Chloride-Induced Corneal Neuropathy","volume":"64","author":"Wu","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4339","DOI":"10.1210\/en.2005-1625","article-title":"Expression and Functional State of the Corticosteroid Receptors and 11 Beta-Hydroxysteroid Dehydrogenase Type 2 in Schwann Cells","volume":"147","author":"Groyer","year":"2006","journal-title":"Endocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bosch-Queralt, M., Fledrich, R., and Stassart, R.M. (2023). Schwann Cell Functions in Peripheral Nerve Development and Repair. Neurobiol. Dis., 176.","DOI":"10.1016\/j.nbd.2022.105952"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/10\/1446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:05:20Z","timestamp":1760130320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/10\/1446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,12]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ph16101446"],"URL":"https:\/\/doi.org\/10.3390\/ph16101446","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,12]]}}}