Abstract
Purpose :
Oxidative stress is a consequence of the accumulation of oxidized proteins, lipids, and nucleic acids. The impact of elevated intraocular pressure (IOP) on the generation of multiple reactive oxygen species (ROS) is determined here in a time course of glaucomatous retina and optic nerve (ON).
Methods :
The DBA/2J (D2) model of glaucoma and its control strain, the DBA/2-Gpnmb+ (D2G) were used. Prior to sacrifice, mice were injected with dihydroethidium (DHE) for superoxide detection. Total retinal ganglion cells (RGCs), ON axons, and anterograde transport of cholera toxin B (CTB) were quantified, hydroxide level was measured, and ON and retina protein were analyzed for p62 and superoxide dismutase 2 (SOD2) normalized to translocase of outer mitochondria (TOM20).
Results :
With IOP elevation (p < 0.0001), ON and retina of 6 and 10 month-old (m) D2 mice showed significant (p < 0.0001) accumulation of superoxide compared to D2G, and a significant decrease in SOD2 protein in ON from 4-6m (p < 0.05) and 10-12m (p < 0.01). Western SOD2 results were supported by immunolabeling in ON and retina. Significant accumulation of hydroxide occurred in ON of 4-6m (p < 0.05) and 10-12m (p < 0.001) D2 compared to D2G mice. The retina of 10m D2 mice showed a significant decrease (p < 0.05) in RGC density and significant axon degeneration (p < 0.05). A significant decrease (p < 0.0001) in anterograde transport of CTB to the superior colliculus (SC) compared to D2G mice was detected. In addition, ON from 10-12m D2 showed a significant increase in p62 compared to 4-6m D2 (p < 0.001), 4-6m D2G (p < 0.05) and 10-12m D2G (p < 0.05).
Conclusions :
We report early (in 4-6m mice) accumulation of superoxide and hydroxide concurrent with IOP elevation, early SOD2 decrease and late (10-12m mice) p62 increase. ROS accumulation preceded neuronal degeneration and transport deficit, which indicates inadequate antioxidant mechanisms that may contribute to glaucoma progression.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.