The Oral Iron Chelator Deferiprone Protects against Iron Overload–Induced Retinal Degeneration

Hadziahmetovic, Majda; Song, Ying; Wolkow, Natalie; Iacovelli, Jared; Grieco, Steven F.; Lee, Jennifer; Lyubarsky, Arkady; Praticò, Domenico; Connelly, John T.; Spino, Michael; Harris, Z. Leah; Dunaief, Joshua L.

doi:10.1167/iovs.10-6207

Cited by 104 publications

(85 citation statements)

References 53 publications

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“…Other researchers reported that DFP decreased retinal labile iron without retinal toxicity in the mouse. 19) These results suggest high ocular safety of DFP.…”

mentioning

confidence: 81%

“…19) In the present study, we histologically and functionally examined whether intravitreal injection of DFP protects against tunicamycin-induced retinal degeneration.…”

mentioning

confidence: 99%

“…18) DFP has also been shown to decrease retinal labile iron without retinal toxicity in the mouse. 19) In the present study, we histologically and functionally examined whether intravitreal injection of DFP protects against tunicamycin-induced retinal degeneration.…”

mentioning

confidence: 99%

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Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Shirai

Mori

Nakahara

et al. 2015

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum stress has been reported to be involved in the pathogenesis of retinitis pigmentosa, macular degeneration and diabetic retinopathy. In the present study, we examined the effects of deferiprone, an iron chelator, on photoreceptor degeneration induced by tunicamycin (300 nmol/eye), an endoplasmic reticulum stress inducer, in the rat retina. Scotopic electroretinogram measurement and morphometric evaluation were done 7 d after the injection of tunicamycin. In the scotopic electroretinogram, intravitreal deferiprone (5 nmol/eye) injected simultaneously with tunicamycin significantly reduced the decreases in aand b-wave amplitudes induced by tunicamycin. Morphometric evaluation showed that deferiprone significantly reduced thinning of the outer nuclear layer, the inner segment and the outer segment. These results suggest that iron chelation therapy may be a good candidate for the treatment of eye diseases related to endoplasmic reticulum stress.Key words deferiprone; tunicamycin; endoplasmic reticulum stress; iron chelation Retinal degeneration involves various ocular disorders that characterized by the progressive death of retinal neurons. Although the mechanisms of photoreceptor cell death are not fully clarified, endoplasmic reticulum (ER) stress is one of candidates that cause macular degeneration, retinitis pigmentosa and diabetic retinopathy. 1) Tunicamycin is an antibiotic that inhibits the biosynthesis of N-acetylglucosaminylpyrophosphoryl polyisoprenol, a key intermediate in the formation of the asparagine-linked oligosaccharides of glycoproteins, 2) and widely known to induce ER stress.3) It has been reported that intravitreal tunicamycin causes photoreceptor-specific degeneration. 4,5) The intravitreal tunicamycin injection model is used for an animal model of photoreceptor-specific degeneration. [6][7][8][9] Increase of reactive oxygen species (ROS) is also known to cause ER stress, Parkinson's disease, 10-12) Alzheimer's disease, [11][12][13] and photoreceptor degeneration. 14) These ROS are believed to be generated at least in part by Fenton reaction, producing hydroxyl radical from hydrogen peroxide. It is well established that labile ferric iron, that does not form a complex with ferritin, is necessary for the Fenton reaction. Previous studies have demonstrated that chemical iron chelators, such as deferoxamine and VK-28, show neuroprotective effects in the animal models of Parkinson's disease 15) and Alzheimer's disease. 16)The aim of the present study was to determine whether iron chelation protects against photoreceptor degeneration induced by tunicamycin. Deferiprone (DFP), a chemical iron chelator that crosses the blood-brain barrier, 17) has shown efficacy with low toxicity in human.18) DFP has also been shown to decrease retinal labile iron without retinal toxicity in the mouse. 19) In the present study, we histologically and functionally examined whether intravitreal injection of DFP protects against tunicamycin-induced retinal degeneration. MATERIALS AND METHODSAnimals E...

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“…Other researchers reported that DFP decreased retinal labile iron without retinal toxicity in the mouse. 19) These results suggest high ocular safety of DFP.…”

mentioning

confidence: 81%

“…19) In the present study, we histologically and functionally examined whether intravitreal injection of DFP protects against tunicamycin-induced retinal degeneration.…”

mentioning

confidence: 99%

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Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Shirai

Mori

Nakahara

et al. 2015

Biological & Pharmaceutical Bulletin

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“…A recent publication has reported beneficial results of oral treatment with the iron chelator deferiprone in a mouse model where it ameliorated oxidative stress and prevented iron overload-induced retinal degeneration [147]. Moreover, several studies on other cultured cell lines have also shown supplementation with iron chelators to make cells less sensitive to H 2 O 2 exposure [148][149][150][151].…”

Section: Iron Chelatorsmentioning

confidence: 99%

Oxidative stress-related damage of retinal pigment epithelial cells : possible protective properties of autophagocytosed iron-binding proteins

Karlsson¹

2015

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“…These authors previously demonstrated that this iron chelator can spare the retina from iron overload-induced degeneration, has no appreciable retinal toxicity in humans or mice, and is readily absorbed upon oral administration. 2 Deferiprone has been used for the management of thalassemia major 3 and is currently in clinical trials in the United States for treatment of contrast-induced acute kidney disease and for slowing the progression of chronic kidney disease (http://www.cormedix.com/pipeline_CRMD001.php). Drug repurposing is a current buzz phrase in translational medicine.…”

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confidence: 99%

Take Two Iron Chelators and Call Me in the Morning

Fliesler

2012

Trans. Vis. Sci. Tech.

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The Oral Iron Chelator Deferiprone Protects against Iron Overload–Induced Retinal Degeneration

Abstract: 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.

Cited by 104 publications

References 53 publications

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Oxidative stress-related damage of retinal pigment epithelial cells : possible protective properties of autophagocytosed iron-binding proteins

Take Two Iron Chelators and Call Me in the Morning

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