Abstract
Purpose :
We recently developed a rigorous and reproducible model of glaucoma in the common marmoset (Callithrix jacchus) (Kumar et al., 2022, TVST). The microbead/occlusion model provides for a consistent elevation of IOP across a 10-week experimental period. Here we tested the hypothesis that the gap junction (GJ)-mediated bystander effect is mechanistically linked to progressive cellular damage in retina and optic nerve associated with glaucoma.
Methods :
Experimental glaucoma in marmosets was initiated by IOP elevation induced by an intracameral injection of 10 µm-diameter polystyrene microbeads. The GJ blocker meclofenamic acid (MFA, 50 mM) was delivered by intravitreal injection weekly for 10 weeks. Functional changes were monitored by ERG recordings and structural changes were assayed by immunohistochemistry and SD-OCT imaging.
Results :
We found that pretreatment of microbead-injected eyes with MFA largely prevented the loss of RGCs normally seen at 10 weeks after IOP elevation. MFA also prevented the loss of RGC axons and disruption of the mosaic structure of the optic nerve observed in microbead-injected eyes. In electrophysiological experiments, we observed a reduction in the photopic negative response (PhNR) beginning at 8 weeks after microbead injection, but no significant change in the a- and b-waves of the ERG. At 10 weeks, the PhNR amplitude continued to decrease, but there was also a significant reduction in amplitude of the a- and b-waves, suggesting a pattern of late damage to photoreceptors and bipolar cells, respectively. However, following MFA application, all ERG components were maintained at control levels in microbead-injected eyes. Finally, we found that MFA prevented the enlarged optic nerve cupping seen in microbead-injected eyes.
Conclusions :
Our results indicate that blockade of GJs offers significant protection of retina and optic nerve in a marmoset model of glaucoma. Taken together with our pervious results from the mouse (Akopian et al., 2017 JCI), the present findings provide further support for our hypothesis that GJs play a critical role in progressive cell death and thereby form novel targets for neuroprotection therapy in glaucoma.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.