Caffeine preferentially protects against oxygen-induced retinopathy

Abstract

Purpose : The clinical observation of the reduced severity of retinopathy of prematurity (ROP) in premature infants after caffeine treatment for sleep apnea raises an exciting possibility that caffeine may protect against pathological retinal neovascularization in ROP via adenosine receptor antagonism. Using the oxygen-induced retinopathy (OIR) model of ROP in mice, we evaluated the efficacy, therapeutic window, the receptor and cellular mechanisms for caffeine to confer protection against OIR.

Methods : We treated the mice with caffeine (0.1-1.0 g/L) with four different treatment paradigms (P0-7, P7-12, P12-17 and P0-17 respectively). Retinal vascularization was examined by whole-mounted fluorescence and cross-sectional hematoxylin-eosin staining. Astrocyte activation and tip cell function in retina were determined by isolectin staining and immunohistochemistry. Retinal apoptosis was determined by TUNEL assay.

Results : Caffeine treatment from P0-P17 dose-dependently and selectively attenuated vaso-obliteration and pathological neovascularization in OIR without interfering normal retinal vascularization. The treatment of caffeine at P7-12 was effective in reducing vaso-obliteration by attenuating neuronal apoptosis while the treatment of caffeine at P7-12 as well as P12-17 was effective in reducing neovascularization by enhancing tip cell function in OIR. A₁Rs was not involved in caffeine’s protection against OIR since A₁R KO exacerbated OIR and administering caffeine to A₁R KO still produced protection against OIR.Caffeine exerted protection against OIR at P12 by acting at the A_2AR-dependent mechanism since both caffeine and A_2AR KO produced similar and partial protection against OIR and the combined caffeine A_2AR KO did not produced further protection. By contrast, caffeine conferred protection at P17 by A_2AR-dependent as well as A_2AR-independent mechanisms since the combined treatment of caffeine and A_2AR produced additional and nearly full protection against OIR on the top of the partial protection by caffeine or A_2AR KO alone.

Conclusions : We have demonstrated the preferential protection against OIR, therapeutic window and A_2AR-dependent and A_2AR-independent mechanisms of caffeine effects in mouse OIR model. Together with widely use of caffeine in neonate care, our findings provide the proof-of-principle evidence to translate the novel caffeine therapy for prevention and treatment of ROP.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.