• Investigative ophthalmology & visual science 10/2012; 53(11):7421-3. DOI:10.1167/iovs.12-10721 · 3.66 Impact Factor
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    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.
    Experimental Eye Research 03/2013; 111. DOI:10.1016/j.exer.2013.03.013 · 3.02 Impact Factor
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    ABSTRACT: Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and β-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the β-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using β-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.
    Acta ophthalmologica 04/2013; 92(1). DOI:10.1111/aos.12049 · 2.51 Impact Factor
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