Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study

Carlo Gesualdo; Cornel Balta; Chiara Bianca Maria Platania; Maria Consiglia Trotta; Hildegard Herman; Sami Gharbia; Marcel Rosu; Francesco Petrillo; Salvatore Giunta; Alberto Della Corte; Paolo Grieco; Rosa Bellavita; Francesca Simonelli; Michele D'Amico; Anca Hermenean; Settimio Rossi; Claudio Bucolo

doi:10.3389/fphar.2021.718902

Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study

Front Pharmacol. 2021 Sep 17:12:718902. doi: 10.3389/fphar.2021.718902. eCollection 2021.

Authors

Carlo Gesualdo¹, Cornel Balta², Chiara Bianca Maria Platania³, Maria Consiglia Trotta⁴, Hildegard Herman², Sami Gharbia², Marcel Rosu², Francesco Petrillo⁵, Salvatore Giunta³, Alberto Della Corte¹, Paolo Grieco⁶, Rosa Bellavita⁶, Francesca Simonelli¹, Michele D'Amico⁴, Anca Hermenean^{2

7}, Settimio Rossi¹, Claudio Bucolo³

Affiliations

¹ Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
² "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania.
³ Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.
⁴ Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁵ Department of Ophthalmology, University of Catania, Catania, Italy.
⁶ Pharmacy Department, University of Naples Federico II, Naples, Italy.
⁷ Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Arad, Romania.

Abstract

This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly (p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors.

Keywords: diabetic retinopathy; fingolimod; melanocortin receptor 1; melanocortin receptor 5; sphingosine 1-phosphate receptor.