# Retinal Neurodegeneration in an Intraocular Pressure Fluctuation Rat Model

## TL;DR

Irregular use of eye drops to lower eye pressure may cause retinal damage through oxidative stress and glial activation.

## Contribution

This study shows that IOP fluctuations, not just high IOP, may contribute to retinal neurodegeneration in glaucoma.

## Key findings

- Irregular instillation of IOP-lowering eyedrops increased oxidative stress markers in rat retinas.
- Macroglial activation was observed in the irregular instillation group, but not microglial activation.
- RGC numbers decreased in the irregular instillation group, likely due to oxidative stress and macrogliosis.

## Abstract

Increased intraocular pressure (IOP) is the most important risk factor for glaucoma. The role of IOP fluctuation, independently from elevated IOP, has not yet been confirmed in glaucoma. We investigated the effects of IOP fluctuation itself on retinal neurodegeneration. Male rats were treated with IOP-lowering eyedrops (brinzolamide and latanoprost) on Mondays and Thursdays (in the irregular instillation group) or daily (in the regular instillation group), and saline was administered daily in the normal control group for 8 weeks. The IOP standard deviation was higher in the irregular instillation group than the regular instillation group or the control group. The degree of oxidative stress, which was analyzed by labeling superoxide, oxidative DNA damage, and nitrotyrosine, was increased in the irregular instillation group. Macroglial activation, expressed by glial fibrillary acidic protein in the optic nerve head and retina, was observed with the irregular instillation of IOP-lowering eyedrops. Microglial activation, as indicated by Iba-1, and the expression of TNF-α did not show a significant difference between the irregular instillation and control groups. Expression of cleaved caspase-3 was upregulated and the number of retinal ganglion cells (RGCs) was decreased in the irregular instillation group. Our findings indicate that IOP fluctuations could be induced by irregular instillation of IOP-lowering eyedrops and this could lead to the degeneration of RGCs, probably through increased oxidative stress and macrogliosis.