Abstract
Purpose :
Retained intraocular foreign bodies containing iron have been linked with glaucoma development and optic nerve atrophy. Elevated levels of iron binding proteins have been found in post mortem retinas from glaucoma patients (PMID 15111596). These findings suggest iron toxicity plays a role in glaucoma pathogenesis. To test this hypothesis, we determined whether systemic treatment with the iron chelator deferiprone (DFP) could protect retinal ganglion cells (RGCs) in two mouse glaucoma models; one genetic and one induced.
Methods :
Twelve DBA/2J mice, a model with high intraocular pressure (IOP) and RGC loss, received water containing 1mg/ml of DFP while an age and sex matched cohort served as control. IOP was tracked from ages 3 to 13 months, at which point animals were euthanized, neural retinas isolated and qPCR performed to measure expressions of RGC-specific genes (Brn3a and Thy1.1) and the antioxidant glutathione peroxidase 4 (Gpx4). In addition, a microbead model was used to elevate IOP in WT mice. Twenty C57BL/6J mice were split into DFP-treated and control groups. One eye of each animal was injected with magnetic microbeads while the fellow eye was injected with saline and served as control.
Results :
Mean±SD IOP of the DBA/2J mice was 16.7±2.0 and 15.3±1.7mmHg (p=0.03) in the DFP-treated and control groups, respectively. Expression of the RGC-specific gene Brn3a was higher in DFP-treated mice compared to controls and the difference was greater in the high IOP (>21mmHg) subgroup (Fig.1A,B). Consistent with this, mRNA level of Thy1.1 was also higher in the high IOP subgroup of the DFP-treated group (Fig.1C,D). We also assessed expression of Gpx4, levels of which are diminished during ferroptosis, an iron-dependent non-apoptotic form of cell death, and found it to be significantly higher in the DFP-treated group (Fig.1E,F). In the WT mice, IOP was elevated in the microbead injected eye (14.26±11.31 vs 9.00±1.72mmHg; p=0.06) 1 week after injections. Assessment of the effects of DFP on RGC-specific genes and RGC cell counts in WT are pending.
Conclusions :
These results suggest iron sequestration may have RGC protective effects in DBA/2J mice in the setting of elevated IOP. Given the increase in Gpx4 expression following DFP treatment, the mechanism by which this occurs may include prevention of ferroptosis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.