Retinal neurodegeneration in intraocular pressure fluctuation rat model

Abstract

Aims/Purpose: The role of IOP fluctuation is controversial in development and progression of glaucoma in clinical trials. We investigated effects of intraocular pressure fluctuation on retinal neurodegeneration and their mechanisms in rats.Methods: Male Sprague–Dawley rats were treated with IOP‐lowering eyedrops (brinzolamide and latanoprost) or saline for 8 weeks. IOP‐lowering eyedrops were put on Monday and Thursday for the irregular instillation group or daily for the regular instillation group, and saline was put daily for the control group. IOP was measured daily under general anaesthesia using a rebound tonometer. Oxidative stress, reaction of microgliosis and the number of retinal ganglion cells (RGCs) were measured.Results: Mean IOP was lower both in the irregular instillation group (9.6 ± 0.4 mmHg) and the regular instillation group (9.5 ± 0.4) than the control group (10.1 ± 0.4 mmHg, p < 0.001). Standard deviation (SD) of IOP was higher in the irregular instillation group (0.8 ± 0.1 mmHg) than the regular instillation group (0.5 ± 0.1 mmHg) or the control group (0.6 ± 0.3 mmHg, p < 0.001). Oxidative stress measured by dihydroethidium, oxidative DNA damage exhibited by 8‐hydroxy‐2′‐deoxyguanosine, and immunostaining for nitrotyrosine were upregulated (All p < 0.001). Expression of glial fibrillary acidic protein in the optic nerve head was more increased in irregular instillation group than the control group, but not in the regular instillation of eyedrops (p = 0.001). Expression of anti‐ionized calcium binding adaptor molecule (Iba‐1), a marker for microglia and P2Y12 known as a chemotactic receptor for microglia did not show a significant difference between the irregular instillation group and the control group. Expression of cleaved caspase‐3 was greater in the irregular instillation group than other two groups (p < 0.001). The number of RGCs stained with anti‐Brn3a antibody was lower in the irregular instillation group than other two groups (p = 0.002).Conclusions: IOP fluctuation induced by treatment of irregular instillation of IOP‐lowering eyedrops reduced the number of RGCs. Our findings indicate that IOP fluctuation induced by treatment of irregular instillation of IOP‐lowering eyedrops could lead to degeneration of RGCs probably by increasing oxidative stress and microgliosis.