Neuroprotection of retinal ganglion cells by agonism of the beta but not the alpha oestrogen receptor in the axotomized retina of male and female mice

Abstract

Purpose

To compare the course of retinal ganglion cell (RGC) loss following optic nerve crush (ONC) in male and female mice and to assess the neuroprotective potential of intravitreally administered oestrogen receptor alpha (ERα) or beta (ERβ) agonists.

Methods

Optic nerve crush was performed on the left optic nerve of male and female C57BL/6 mice. RGC loss was evaluated at 3–21 days post-lesion. ERα and ERβ agonists (PPT and DPN, respectively) were injected either immediately after ONC with retinas analysed at 5 days or immediately post-ONC and again at 9 days, with retinas analysed at 21 days post-lesion. Intact retinas served as controls. The total population of Brn3a⁺RGCs was quantified in retinal flat mounts. To assess the retinal expression of ERα and ERβ, immunodetection was performed on cross sections, and the percentage of RGCs expressing each receptor was determined in flat mounts.

Results

Retinal ganglion cell loss in both sexes followed two distinct linear phases: A rapid phase up to 9 days post-lesion, followed by a slower phase. However, the onset of RGC loss was earlier in males than in females. Both ERα and ERβ were expressed in all retinal layers and by the majority of RGCs. While ERα agonism did not confer RGC protection, ERβ agonism was neuroprotective during the second phase of axotomy-induced RGC loss.

Conclusions

Preclinical results may be influenced by pooling data from male and female mice. The neuroprotective effects of ERβ during the second phase of RGC loss, likely linked to neuroinflammation, suggest potential therapeutic applications for chronic conditions such as glaucoma.