Adenosine A1 receptor: A neuroprotective target in light induced retinal degeneration.

Manuel Soliño,Manuel Rey-Funes,Elena Girardi,Ignacio M Larrayoz,Ester María López,Alfredo Martínez,César Fabián Loidl,Juan José López-Costa

doi:10.1371/journal.pone.0198838

Abstract

Light induced retinal degeneration (LIRD) is a useful model that resembles human retinal degenerative diseases. The modulation of adenosine A1 receptor is neuroprotective in different models of retinal injury. The aim of this work was to evaluate the potential neuroprotective effect of the modulation of A1 receptor in LIRD. The eyes of rats intravitreally injected with N6-cyclopentyladenosine (CPA), an A1 agonist, which were later subjected to continuous illumination (CI) for 24 h, showed retinas with a lower number of apoptotic nuclei and a decrease of Glial Fibrillary Acidic Protein (GFAP) immunoreactive area than controls. Lower levels of activated Caspase 3 and GFAP were demonstrated by Western Blot (WB) in treated animals. Also a decrease of iNOS, TNFα and GFAP mRNA was demonstrated by RT-PCR. A decrease of Iba 1+/MHC-II+ reactive microglial cells was shown by immunohistochemistry. Electroretinograms (ERG) showed higher amplitudes of a-wave, b-wave and oscillatory potentials after CI compared to controls. Conversely, the eyes of rats intravitreally injected with dipropylcyclopentylxanthine (DPCPX), an A1 antagonist, and subjected to CI for 24 h, showed retinas with a higher number of apoptotic nuclei and an increase of GFAP immunoreactive area compared to controls. Also, higher levels of activated Caspase 3 and GFAP were demonstrated by Western Blot. The mRNA levels of iNOS, nNOS and inflammatory cytokines (IL-1β and TNFα) were not modified by DPCPX treatment. An increase of Iba 1+/MHC-II+ reactive microglial cells was shown by immunohistochemistry. ERG showed that the amplitudes of a-wave, b-wave, and oscillatory potentials after CI were similar to control values. A single pharmacological intervention prior illumination stress was able to swing retinal fate in opposite directions: CPA was neuroprotective, while DPCPX worsened retinal damage. In summary, A1 receptor agonism is a plausible neuroprotective strategy in LIRD.

Highlights

Human retinal degenerative diseases are important disabling conditions
Recent articles have shown the neuroprotective effect of peptides such as pituitary adenylate cyclase-activating peptide (PACAP) and the octapeptide NAP, derived from activity-dependent neuropeptide protein (ADNP), in rat diabetic retinopathy which counteract the up-regulation of vascular endothelial growth factor (VEGF) [4, 5]
No transferase dUTP nick end labeling (TUNEL) positive nuclei were found in control eyes before illumination, but after 1 day of continuous illumination (CI), apoptotic nuclei were found in retinal outer nuclear layer (ONL) in both experimental conditions (CPA and control)

Summary

Introduction

Human retinal degenerative diseases are important disabling conditions. Current treatments for dry AMD slow down or prevent additional vision loss to some extent but they do not restore lost vision. The majority of patients require indefinite treatment or demonstrate disease progression despite therapies [2]. A meta-analysis shows that 20–25% of unilateral AMD cases, and up to 50% of unilateral late AMD cases progress to bilateral in 5 years [3]. These evidences show the importance of exploring other pharmacological tools to deal with retinal degenerative diseases. Recent articles have shown the neuroprotective effect of peptides such as pituitary adenylate cyclase-activating peptide (PACAP) and the octapeptide NAP, derived from activity-dependent neuropeptide protein (ADNP), in rat diabetic retinopathy which counteract the up-regulation of VEGF [4, 5]

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