Siponimod as a novel inhibitor of retinal angiogenesis: In vitro and in vivo evidence of therapeutic efficacy

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dc.check.date2024-08-01en
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorAlshaikh, Rasha A.en
dc.contributor.authorGamal Eldin Zaki, Raniaen
dc.contributor.authorSalah El Din, Rania A.en
dc.contributor.authorRyan, Katie B.en
dc.contributor.authorWaeber, Christianen
dc.contributor.funderIrish Research Councilen
dc.date.accessioned2023-09-05T11:50:47Z
dc.date.available2023-09-05T11:50:47Z
dc.date.issued2023-08-01en
dc.description.abstractSphingosine-1-phosphate (S1P) receptors control endothelial cell proliferation, migration, and survival. Evidence of the ability of S1P receptor modulators to influence multiple endothelial cell functions suggests their potential use for antiangiogenic effect. The main purpose of our study was to investigate the potential of siponimod for the inhibition of ocular angiogenesis in vitro and in vivo. We investigated the effects of siponimod on the metabolic activity (thiazolyl blue tetrazolium bromide assay), cell toxicity (lactate dehydrogenase release), basal proliferation and growth factor–induced proliferation (bromodeoxyuridine assay), and migration (transwell migration assay) of human umbilical vein endothelial cells (HUVEC) and retinal microvascular endothelial cells (HRMEC). The effects of siponimod on HRMEC monolayer integrity, barrier function under basal conditions, and tumor necrosis factor alpha (TNF-α)-induced disruption were assessed using the transendothelial electrical resistance and fluorescein isothiocyanate–dextran permeability assays. Siponimod’s effect on TNF-α–induced distribution of barrier proteins in HRMEC was investigated using immunofluorescence. Finally, the effect of siponimod on ocular neovascularization in vivo was assessed using suture-induced corneal neovascularization in albino rabbits. Our results show that siponimod did not affect endothelial cell proliferation or metabolic activity but significantly inhibited endothelial cell migration, increased HRMEC barrier integrity, and reduced TNF-α–induced barrier disruption. Siponimod also protected against TNF-α–induced disruption of claudin-5, zonula occludens-1, and vascular endothelial–cadherin in HRMEC. These actions are mainly mediated by sphingosine-1-phosphate receptor 1 modulation. Finally, siponimod prevented the progression of suture-induced corneal neovascularization in albino rabbits. In conclusion, the effects of siponimod on various processes known to be involved in angiogenesis support its therapeutic potential in disorders associated with ocular neovascularization.en
dc.description.sponsorshipIrish Research Council (GOIPG/2020/971)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAlshaikh, R. A., Gamal Eldin Zaki, R., Salah El Din, R. A., Ryan, K. B. and Waeber, C. (2023) 'Siponimod as a novel inhibitor of retinal angiogenesis: In vitro and in vivo evidence of therapeutic efficacy', Journal of Pharmacology and Experimental Therapeutics, 386(2), pp. 224-241. doi: 10.1124/jpet.122.001529en
dc.identifier.doi10.1124/jpet.122.001529en
dc.identifier.eissn1521-0103en
dc.identifier.endpage241en
dc.identifier.issn0022-3565en
dc.identifier.issued2en
dc.identifier.journaltitleJournal of Pharmacology and Experimental Therapeuticsen
dc.identifier.startpage224en
dc.identifier.urihttps://hdl.handle.net/10468/14906
dc.identifier.volume386en
dc.language.isoenen
dc.publisherAmerican Society for Pharmacology and Experimental Therapeuticsen
dc.rights© 2023, The American Society for Pharmacology and Experimental Therapeutics.en
dc.subjectBAF 312en
dc.subjectDiabetes Mellitusen
dc.subjectDiabetic retinopathyen
dc.subjectAge-related macular degenerationen
dc.subjectSphingosine 1-phosphateen
dc.subjectCorneal neovascularizationen
dc.titleSiponimod as a novel inhibitor of retinal angiogenesis: In vitro and in vivo evidence of therapeutic efficacyen
dc.typeArticle (peer-reviewed)en
oaire.citation.issue2en
oaire.citation.volume386en
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