Propranolol inhibition of beta-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy

• PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective beta-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of beta-adrenergic receptors is an appropriate therapeutic approach for treating ROP.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Annan medicin och hälsovetenskap (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Other Medical and Health Sciences (hsv//eng)

Nyckelord

Administration

Oral

Adrenergic beta-Antagonists/*administration & dosage

Angiopoietin-1/genetics/metabolism

Angiopoietin-2/genetics/metabolism

Animals

Animals

Newborn

Cell Proliferation

Disease Models

Animal

Dose-Response Relationship

Drug

Drug Evaluation

Preclinical

Endothelial Cells/drug effects

Enzyme-Linked Immunosorbent Assay

Erythropoietin/genetics/metabolism

Gene Expression Profiling

Humans

Infant

Newborn

Injections

Intraperitoneal

Injections

Subcutaneous

Mice

Oxygen/toxicity

Propranolol/*administration & dosage

RNA/metabolism

Receptors

Adrenergic

beta/metabolism

Receptors

Vascular Endothelial Growth Factor/genetics/metabolism

Retina/cytology

Retinal Neovascularization/metabolism/*prevention & control

Retinopathy of Prematurity/metabolism/*prevention & control

Reverse Transcriptase Polymerase Chain Reaction

Up-Regulation

Vascular Endothelial Growth Factor A/genetics/metabolism

Publikations- och innehållstyp

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