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M. Hadziahmetovic, Y. Song, S. Grieco, S. Kusko, D. Pratico, J. L. Dunaief; Iron Chelator Deferiprone Protects Against Iron Mediated Oxidative Stress and Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2981.
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Iron is essential for normal retinal function, but also a potent generator of oxidative stress if present in excess, especially in the form of labile (free) iron. Several lines of evidence suggest iron toxicity may exacerbate AMD. First, AMD retinas have elevated iron levels. Second, patients with elevated retinal iron levels due to mutation in the ferroxidase ceruloplasmin have early onset macular degeneration. Third, mice with mutations in ceruloplasmin and its homolog hephaestin (DKO mice) have an age-dependent retinal iron accumulation with subsequent retinal degeneration sharing features of AMD. Deferiprone is an orally absorbed, low-molecular weight iron chelator that can cross the blood-brain barrier and decrease brain iron levels in patients with Friedreich’s Ataxia. The purpose of this study was to test whether iron chelation is protective against oxidative stress induced retinal degeneration mediated by labile iron.
Morphological analysis was performed on retina sections from Deferiprone treated and untreated age-matched DKO mice. Transferrin Receptor (TfR) was used as an indirect measure of labile iron chelation; its mRNA levels were assessed by qPCR. Immunofluoresence was performed with antibodies detecting TfR. Isoprostane F2alpha-VI, a quantitative marker of oxidative stress in the retina was measured by gas chromatography/mass spectrometry.
Systemic administration of Deferiprone increases neural retinal TfR mRNA levels, provides marked protection against retinal degeneration in iron overloaded DKO mice while decreasing oxidative stress, increases their hematocrit and prolongs their lifespan. When given as an eye drop, Deferiprone increases TfR mRNA in the cornea, lens, and RPE/choroid.
Deferiprone can penetrate the eye and chelate labile iron when given orally or topically. It can protect the retina against iron overload induced retinal degeneration. It may be protective in eye diseases involving oxidative stress such as AMD and glaucoma.
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