Iron Chelation Protects Against Murine Retinal Degeneration Induced Through Diverse Mechanisms

Abstract

Purpose: : Iron is a potent generator of oxidative stress. We have shown previously that the oral iron chelator deferiprone (DFP) can protect against iron overload-induced retinal degeneration in Cp/Heph mice. Herein, we test whether DFP can be retina-protective in three mouse models where iron overload is not the primary cause of retinal degeneration.

Methods: : For light-induced oxidative damage A/J mice were gavaged with 75mg/kg DFP bid, or with saline (n = 4 each) and exposed to 10,000 lux cool white fluorescent light for 20 hours. Mice were sacrificed at different time points after light exposure. For NaIO₃-induced retinal degeneration, C57BL/6 mice were gavaged with 75mg/kg DFP bid or saline for 7 days before and after tail vein injection of 25mg/kg NaIO₃. Four-week old rd6 mice were exposed to drinking water with or without 1 mg/ml DFP (n = 4 each, approximate daily dose of 150mg/kg) for 6 months prior to sacrifice. Neurosensory retinas (NSR) and RPE were collected, and RNA was isolated. Gene expression was assessed using RT-PCR. Photoreceptor apoptosis was assessed using the TUNEL assay. Immunofluorescence was performed with antibodies detecting microglia/macrophage marker Iba1 and tight junction protein ZO-1. Retinal degeneration was assessed by histology.

Results: : Upregulation of retinal mRNA levels of oxidative stress-related genes and C3 by light exposure was partially prevented by DFP treatment. Robust microglial migration to the outer retina that occurred after light exposure was reduced by DFP treatment, as was the number of TUNEL-positive photoreceptors. In NaIO₃-treated mice, DFP treatment protected against photoreceptor loss, decreased expression of oxidative stress-related genes and C3, and significantly increased markers of photoreceptor and RPE health, rhodopsin and RPE65. Retinal histology of rd6 mice (a model of hereditary retinal degeneration) treated with DFP showed partial protection against loss of photoreceptors.

Conclusions: : This study provides evidence that DFP provides retinal protection in light, chemical oxidant (NaIO₃), and mutation (rd6)-induced retinal degeneration in which iron dysregulation is not the primary culprit, perhaps by diminishing oxidative stress. These data suggest that iron chelation should be explored as a potential treatment for retinal degeneration induced by a variety of insults.

Keywords: antioxidants • cell survival • retinal degenerations: cell biology