Abstract
Purpose :
Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic nerve-related cause of vision loss in people over age 50; however, NAION has no proven treatment. Previously, we demonstrated that interleukin-6 (IL-6) is upregulated in an experimental rodent model of NAION (rNAION), based on deep sequencing data from rat optic nerve and retinal tissue. In this experiment, we tested the hypothesis that IL-6 inhibition would decrease inflammatory response and preserve retinal ganglion cells (RGCs) in the rNAION model.
Methods :
rNAION was induced in 4 adult male Sprague-Dawley rats. On post-induction day 1, optic nerve edema was assessed by slit lamp and optical coherence tomography (OCT), and animals were paired in terms of similar amounts of edema. One from each pair was treated with subcutaneous sarilumab (human IL-6 inhibitor), whereas the others received vehicle (saline). At 1 week post-induction, rats were euthanized, and eyes and optic nerves were isolated and post-fixed in 4% paraformaldehyde-PBS. Post-fixed retinas were isolated, and RGCs immunostained with Brn3a antibody. Cryopreserved optic nerve laminar sections were immunostained with Iba1 (for microglia), CD68 (for macrophages), and SMI312 (for neurofilaments).
Results :
There was no appreciable reduction in resident microglia or extrinsic macrophage recruitment (Figure 1) and no appreciable RGC preservation (Figure 2) in rNAION animals treated with sarilumab compared with controls.
Conclusions :
IL-6 inhibition does not appear to reduce inflammatory cell recruitment or to preserve RGCs in rNAION, when administered 1 day after disease-state induction, despite known IL-6 upregulation in this disease model. Possible explanations for this finding include (1) a narrow time window for therapeutic anti-inflammatory treatment in rNAION, in which case this treatment avenue is not likely to be clinically relevant; (2) the IL-6 response is a nonspecific inflammatory epiphenomenon and may not specifically modulate damage-inducing inflammation in rNAION; or (3) the fully humanized sarilumab antibody is functionally limited in its effects in rat. Further study with a rodentized IL-6 inhibitor may further elucidate the role of IL-6 inhibition in rNAION.
This is a 2021 ARVO Annual Meeting abstract.