Adenosine A3 receptor agonist prevents the loss of retinal ganglion cells in a glaucoma model

Abstract

Purpose : Glaucoma is a leading cause of irreversible blindness and current treatments target the lowering of intraocular pressure (IOP). In some patients, vision loss progresses despite successful IOP control, indicating that new and effective treatments are needed, such as those targeting neuroprotection of retinal ganglion cells (RGCs). Adenosine A3 receptor (A3R) activation confers protection to RGCs following excitotoxic stimuli. In this work, we investigated whether the activation of A3R could also afford RGC protection in a well characterized animal model of glaucoma.

Methods : Ocular hypertension (OHT) was induced by laser photocoagulation of the limbal veins and the A3R agonist (2-Cl-IB-MECA) was delivered intravitreally immediately after surgery. The retrograde axonal transport was determined by application of Fluorogold (FG) in both superior colliculi. Electroretinography was performed after 7 days of OHT induction to assess retinal electrical activity. The survival of RGCs was assessed in whole-mounted retinas by Brn3a immunodetection.

Results : The assessment of retinal function demonstrated that OHT induced a significant decrease in scotopic threshold response (STR), a- and b-wave amplitudes. The A3R agonist prevented the alterations induced by OHT in STR (p<0.05), without changing a- and b-wave amplitudes in scotopic conditions. Moreover, the treatment with the A3R agonist significantly decreased the loss of RGCs induced by OHT (p<0.05) and attenuated the impairment in retrograde axonal transport induced by OHT.

Conclusions : Our results show that 2-Cl-IB-MECA increased the RGC survival in OHT animals. Taking into consideration the beneficial effect of A3R agonist, we can envisage that A3R can be considered a good therapeutic target to protect RGCs from glaucomatous damage.

Support: FCT (PD/BD/114115/2015, Grant PTDC/NEU-OSD/3123/2014 and Strategic Project UID/NEU/04539/2013), FEDER-COMPETE (FCOMP-01-0124-FEDER-028417 and POCI-01-0145-FEDER-007440) and Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000008: BrainHealth 2020), Portugal.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.