Inhibition Of β-adrenergic Receptor With Propranolol Does Not Protect Against Oxygen-induced Retinopathy

Abstract

Purpose: : Retinopathy of prematurity (ROP) is a leading cause of blindness in children characterized by vision-threatening pathologic vessels. Propranolol, a non-selective β-adrenergic receptor blocker, has been serendipitously identified as a new treatment for infantile hemangioma, a type of benign tumor with vascular elements, with some severe side effects reported. Interestingly in a mouse model of oxygen-induced ROP (OIR), propranolol was reported to be effective in protecting against pathologic retinal neovascularization, although retinopathy was evaluated with non-standard techniques. Based on this single report, a clinical trial (PROP-ROP) is currently ongoing to evaluate propranolol treatment in ROP patients. Because of the fragility of incompletely developed premature infants the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in pre-clinical animal models of retinopathy, which is the focus of this study.

Methods: : Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to 12. Two doses of propranolol (2 or 20mg/kg/day) were given daily from P13 to P16. Three routes of invention were assessed: oral gavage, intraperitoneal injection or subcutaneous injection. At P17, per standard protocol, retinas were flatmounted and stained with lectin to visualize vaso-obliteration (VO) and pathologic neovascularization (NV). Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol treated pups.

Results: : There was no difference in either VO or in pathologic NV in OIR at P17 with oral gavage of propranolol at 2mg/kg/day (equivalent to the standard human dose), nor with intraperitoneal injection of propranolol at the same dose. A higher dose of propranolol (20mg/kg/day) injected subcutaneously was not effective in suppressing either VO or NV in OIR. Importantly, intraperitoneal injection of propranolol at 20mg/kg/day was associated with a modest but significant increase in both VO and NV in retinopathy.

Conclusions: : Propranolol treatment via three routes and up to 10 times the standard human dose fails to suppress retinopathy development in mice. These data bring into question whether propranolol and inhibition of beta-adrenergic receptors is a viable therapeutic approach for treating ROP.

Keywords: retinopathy of prematurity • retinal neovascularization • hypoxia