The Protective Effects of Endogenous PACAP in Oxygen-induced Retinopathy 

Abstract Purpose: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide having trophic and protective functions in neural tissues including the retina. Previously we have shown that intravitreal PACAP administration can maintain retinal structure in the animal model of retinopathy of prematurity (ROP). The purpose of this study is to examine the development of ROP in PACAP-deficient and wild-type mice to reveal the function of endogenous PACAP. Methods: Wild-type and PACAP-KO mouse pups at postnatal day (PD) 7 were maintained at 80% oxygen for 5 consecutive days then returned to room air on PD12 to develop oxygen-induced retinopathy (OIR). On PD15 animals underwent electroretinography (ERG) to assess visual function. On PD16 eyes were harvested for either immunohistochemistry to determine the percentage of central avascular retinal area and neovascular tuft formation or molecular analysis to assess angiogenesis proteins by array kit and antiapoptotic protein kinase B (Akt) change by western blot. Results: The retina of PACAP deficient OIR mice showed greater central avascular area than that of the wild types. ERG revealed significantly decreased b-wave amplitude in PACAP KO compared to their controls. Several angiogenic proteins were upregulated as a results of OIR and 11 further proteins markedly increased in PACAP deficient mice. Conclusion: This is the first study to examine the endogenous effect of PACAP in OIR model. Previously we have shown the beneficial effect of exogenous local PACAP treatment in the rat OIR model. Together with the present findings we suppose that PACAP could be a novel retinoprotective agent in ROP.