J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07530.x Oxygen‐induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta‐adrenergic receptor (β‐AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct β‐ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β₂‐AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β₁‐ and β₃‐AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β‐AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, β₂‐AR silencing prevents ICI 118,551 effects on hypoxia‐induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of β₂‐ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β₂‐ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that β₂‐ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision‐threatening retinal diseases, depends at least in part on β₂‐AR activity and indicate that β₂‐AR blockade can be effective against retinal angiogenesis.

Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment. In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy. Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests. This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies. Current Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21

There is indication that nutritional supplements protect retinal cells from degeneration. In a previous study, we demonstrated that dietary supplementation with an association of forskolin, homotaurine, spearmint extract and B vitamins efficiently counteracts retinal dysfunction associated with retinal ganglion cell (RGC) death caused by optic nerve crush. We extended our investigation on the efficacy of dietary supplementation with the use of a mouse model in which RGC degeneration depends as closely as possible on intraocular pressure (IOP) elevation. In this model, injecting the anterior chamber of the eye with methylcellulose (MCE) causes IOP elevation leading to RGC dysfunction. The MCE model was characterized in terms of IOP elevation, retinal dysfunction as determined by electrophysiological recordings, RGC loss as determined by brain-specific homeobox/POU domain protein 3A immunoreactivity and dysregulated levels of inflammatory and apoptotic markers. Except for IOP elevation, dysfunctional retinal parameters were all recovered by dietary supplementation indicating the involvement of non-IOP-related neuroprotective mechanisms of action. Our hypothesis is that the diet supplement may be used to counteract the inflammatory processes triggered by glial cell activation, thus leading to spared RGC loss and the preservation of visual dysfunction. In this respect, the present compound may be viewed as a potential remedy to be added to the currently approved drug therapies for improving RGC protection.