title: Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy.
abstract: OBJECTIVE
  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 β-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 β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jean-Sebastian
authors.initials: JS
authors.lastname: Joyal
authors.forename: Colman J
authors.initials: CJ
authors.lastname: Hatton
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.forename: Dorothy T
authors.initials: DT
authors.lastname: Pei
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hurst
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Ann
authors.initials: A
authors.lastname: Hellstrom
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D051379:Mice; D010100:Oxygen / Q000633:toxicity; D011433:Propranolol / Q000008:administration & dosage*; D012313:RNA / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology; D015861:Retinal Neovascularization / Q000378:metabolism / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D012313:RNA; D011433:Propranolol; D040262:Receptors, Vascular Endothelial Growth Factor; D010100:Oxygen