title: The oral iron chelator deferiprone protects against systemic iron overload-induced retinal degeneration in hepcidin knockout mice.
abstract: OBJECTIVE
  To investigate the retinal-protective effects of the oral iron chelator deferiprone (DFP) in mice lacking the iron regulatory hormone hepcidin (Hepc). These Hepc knockout (KO) mice have age-dependent systemic and retinal iron accumulation leading to retinal degeneration.
  
  
  METHODS
  Hepc KO mice were given DFP in drinking water from age 6 to 18 months. They were then compared to Hepc KO mice not receiving DFP by fundus imaging, electroretinography (ERG), histology, immunofluorescence, and quantitative PCR to investigate the protective effect of DFP against retinal and retinal pigment epithelial (RPE) degeneration.
  
  
  RESULTS
  In Hepc KO mice, DFP diminished RPE depigmentation and autofluorescence on fundus imaging. Autofluorescence in the RPE layer in cryosections was significantly diminished by DFP, consistent with the fundus images. Immunolabeling with L-ferritin and transferrin receptor antibodies showed a decreased signal for L-ferritin in the inner retina and RPE cells and an increased signal for transferrin receptor in the inner retina, indicating diminished retinal iron levels with DFP treatment. Plastic sections showed that photoreceptor and RPE cells were well preserved in Hepc KO mice treated with DFP. Consistent with photoreceptor protection, the mRNA level of rhodopsin was significantly higher in retinas treated with DFP. The mRNA levels of oxidative stress-related genes heme oxygenase-1 and catalase were significantly lower in DFP-treated Hepc KO retinas. Finally, ERG rod a- and b- and cone b-wave amplitudes were significantly higher in DFP-treated mice.
  
  
  CONCLUSIONS
  Long-term treatment with the oral iron chelator DFP diminished retinal and RPE iron levels and oxidative stress, providing significant protection against retinal degeneration caused by chronic systemic iron overload in Hepc KO mice. This indicates that iron chelation could be a long-term preventive treatment for retinal disease involving iron overload and oxidative stress.
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Delu
authors: D
authors: Song
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania Department of Ophthalmology, Second Hospital of Jilin University, Changchun, China.
authors: Liangliang
authors: L
authors: Zhao
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Yafeng
authors: Y
authors: Li
authors: Department of Ophthalmology, Drexel University School of Medicine, Philadelphia, Pennsylvania.
authors: Majda
authors: M
authors: Hadziahmetovic
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Ying
authors: Y
authors: Song
authors: ApoPharma, Inc., Toronto, Canada.
authors: John
authors: J
authors: Connelly
authors: ApoPharma, Inc., Toronto, Canada Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
authors: Michael
authors: M
authors: Spino
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Joshua L
authors: JL
authors: Dunaief
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000077543:Deferiprone; D004195:Disease Models, Animal; D004596:Electroretinography; D005293:Ferritins / Q000378:metabolism; D005451:Fluorescein Angiography; D019084:Fluorescent Antibody Technique, Indirect; D051547:Heme Oxygenase-1 / Q000235:genetics; D064451:Hepcidins / Q000502:physiology*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061848:Optical Imaging; D018384:Oxidative Stress; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011990:Receptors, Transferrin / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics
chemical_list: D064451:Hepcidins; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D011728:Pyridones; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D000077543:Deferiprone; D005293:Ferritins; D012243:Rhodopsin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: deferiprone; hepcidin; oxidative stress; retinal degeneration