Abstract
Purpose :
Retinal diseases that damage photoreceptors, particularly those that affect cones such as the “dry” form of age-related macular degeneration (AMD), have dire consequences for vision. Models of light-induced retinal degeneration (LIRD) recapitulate some of the damage observed in dry AMD. One strategy for treating AMD is to utilize a “druggable” therapy targeted to neuroprotective mechanisms in photoreceptors. Adenosine has neuroprotective properties at neurons within the central nervous system and prevents neurodegeneration. The purpose of this study was to determine which adenosine receptors mediate neuroprotection of photoreceptors in a zebrafish LIRD model.
Methods :
Adult wild-type and Tg(nrd:GFP) zebrafish were dark-adapted for 24 hours, followed by intravitreal injections of adenosine or adenosine receptor agonists (A1R, A2AR, A2BR, A3R). Controls were injected with saline in both eyes. All zebrafish were exposed to high-intensity light (28,000 lux) and collected at 0 and 96 hours post dark-adaptation. Immunohistochemical analysis with cell specific markers, TUNEL assays, and optomotor response measurements were performed on zebrafish in order to assess the impact of adenosine and adenosine receptor agonists on LIRD.
Results :
Treatment of retinas with adenosine resulted in a dose-dependent survival of both rod and cone photoreceptors after LIRD that was mediated by both A1R and A3R in the retina. Any damage observed in adenosine-treated retinas was not enough to stimulate a regenerative response, arguing in favor of a neuroprotective mechanism. Moreover, higher concentrations of adenosine prevented structural damage and apoptosis of rods and cones while preserving both visual acuity and contrast sensitivity in zebrafish retinas, suggesting that adenosine has the capacity to preserve photoreceptor function.
Conclusions :
These findings clearly demonstrate that adenosine acting on A1R and A3R has a significant capacity for neuroprotection and provides evidence of a potential novel therapeutic target for the treatment of the dry form of AMD.
This is a 2021 ARVO Annual Meeting abstract.