The oral iron chelator deferiprone protects iron overload-induced retinal degeneration. Invest Ophthalmol Vis Sci 52:959–968

Abstract

PURPOSE. Iron-induced oxidative stress may exacerbate agerelated macular degeneration (AMD). Ceruloplasmin/Hephaestin double-knockout (DKO) mice with age-dependent retinal iron accumulation and some features of AMD were used to test retinal protection by the oral iron chelator deferiprone (DFP). METHODS. Cultured retinal pigment epithelial (ARPE-19) cells and mice were treated with DFP. Transferrin receptor mRNA (Tfrc), an indicator of iron levels, was quantified by qPCR. In mice, retinal oxidative stress was assessed by mass spectrometry, and degeneration by histology and electroretinography. RESULTS. DFP at 60 M decreased labile iron in ARPE-19 cells, increasing Tfrc and protecting 70% of cells against a lethal dose of H 2 O 2 . DFP 1 mg/mL in drinking water increased retinal Tfrc mRNA 2.7-fold after 11 days and also increased transferrin receptor protein. In DKOs, DFP over 8 months decreased retinal iron levels to 72% of untreated mice, diminished retinal oxidative stress to 70% of the untreated level, and markedly ameliorated retinal degeneration. DFP was not retina toxic in wild-type (WT) or DKO mice, as assessed by histology and electroretinography. CONCLUSIONS. Oral DFP was not toxic to the mouse retina. It diminished retinal iron levels and oxidative stress and protected DKO mice against iron overload-induced retinal degeneration. Further testing of DFP for retinal disease involving oxidative stress is warranted. (Invest Ophthalmol Vis Sci. 2011;52:959 -968) DOI:10.1167/iovs.10-6207 I ron is crucial for optimal cellular metabolism, but is also a potent generator of oxidative stress if present in excess, especially in the form of labile ferrous iron. Inability of the body to actively excrete excess iron leads to age-dependent iron accumulation in certain tissues, including the macula. 1 Excess tissue iron generates reactive oxygen species (ROS) via the Fenton reaction, leading to oxidative damage. Free radicals and oxidative stress have been implicated in a growing number of conditions, from normal aging to cancer, diabetes, and neurodegenerative diseases, making iron overload or metabolic mishandling of iron an important target for therapeutic intervention. 2-6 Since iron catalyzes the production of the hydroxyl radical, the most damaging of the free radicals, it is likely to exacerbate oxidative damage in a tissue that is already prone to oxidative insult. Retinal pigment epithelial (RPE) cells and photoreceptors are especially vulnerable to oxidative damage due to high oxygen tension, ROS production by large numbers of mitochondria, and abundant, easily oxidized polyunsaturated fatty acids in photoreceptor membranes. 7 Indeed, several neurodegenerative disorders with iron dysregulation feature retinal degeneration. 8 These include the rare hereditary disorders aceruloplasminemia, Friedreich's ataxia, and pantothenate kinase-associated neurodegeneration. Further, traumatic siderosis causes rapid retinal degeneration. 9 Similarly, retinal degeneration in several mouse models is associated with retinal iron dysregulation. -12 Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the elderly worldwide. Although the pathogenesis of AMD is incompletely understood, growing evidence suggests that, in addition to inflammation, complement activation, and other hereditary and environmental influences, 9 Supporting this hypothesis, patients lacking the ferroxidase ceruloplasmin (Cp) as a result of the autosomal recessive condition aceruloplasminemia, have retinal iron accumulation and early-onset macular degeneration. From th