title: Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice.
abstract: The mouse model of oxygen-induced retinopathy (OIR) is a well-established model of retinopathy of prematurity (ROP), characterized by the abnormal formation of new blood vessels, which is similar to ROP. In this model, we have recently shown that subcutaneous (sc) administration of the non-selective beta-adrenergic receptor (β-AR) blocker propranolol ameliorates angiogenic processes in the retina when its effects are evaluated at postnatal day (PD) 17. In the present study, we investigated whether propranolol application as collyrium can promote the recovery of OIR. After propranolol administration on the eye, mice were first tested for retinal concentrations of propranolol as compared with those measured after sc or per os administration. Subsequently, we determined the effects of propranolol ophthalmic solutions, at the optimal dose for delivery, on VEGF, IGF-1, hypoxia-inducible factor (HIF)-1α, signal transducer and activator of transcription 3 (STAT3) and retinal neovascularization as assessed in both the superficial and the deep vascular plexuses. The results showed that 2% topical propranolol has an efficiency (in terms of final propranolol concentration in the retina) comparable to that of 20 mg/kg propranolol sc or per os and significantly higher than those observed with doses and administration routes that are currently used with children. Propranolol ophthalmic solutions reduced VEGF and IGF-1 up-regulation in response to hypoxia and drastically inhibited HIF-1α accumulation and STAT3 phosphorylation. As a result of its inhibitory effects on hypoxia-induced proangiogenic factors, propranolol significantly reduced retinal neovascularization in the superficial but not in the deep vascular plexus. An evaluation of retinal neovascularization at PD21 showed that propranolol was still effective in inhibiting OIR. These findings strengthen the hypothesis that β-AR blockade can efficiently counteract OIR and suggest that topical eye application of propranolol can represent an alternative delivery route to systemic administration thus avoiding the risk of associated complications and side effects that could make this drug unsafe in the ROP treatment.
authors.affiliation: Department of Biology, University of Pisa, via San Zeno, 31, 56127 Pisa, Italy. mdalmonte@biologia.unipi.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Dal Monte
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.forename: Benedetta
authors.initials: B
authors.lastname: Isacchi
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D051379:Mice; D009883:Ophthalmic Solutions / Q000494:pharmacology*; D010100:Oxygen / Q000633:toxicity*; D011433:Propranolol / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000473:pathology; D012269:Ribosomal Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000319:Adrenergic beta-Antagonists; D009883:Ophthalmic Solutions; D012269:Ribosomal Proteins; C520792:Rpl13a protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D007334:Insulin-Like Growth Factor I; D011433:Propranolol; D010100:Oxygen