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.