The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration.
OBJECTIVE
Iron-induced oxidative stress may exacerbate age-related 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 μM 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.
F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Majda
M
Hadziahmetovic
Ying
Y
Song
Natalie
N
Wolkow
Jared
J
Iacovelli
Steven
S
Grieco
Jennifer
J
Lee
Arkady
A
Lyubarsky
Domenico
D
Pratico
John
J
Connelly
Michael
M
Spino
Z Leah
ZL
Harris
Joshua L
JL
Dunaief
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002570:Ceruloplasmin / Q000235:genetics; D000077543:Deferiprone; D004596:Electroretinography; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; C068126:CD71 antigen; D007502:Iron Chelating Agents; D011728:Pyridones; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000077543:Deferiprone; D006861:Hydrogen Peroxide; D002570:Ceruloplasmin