Overexpressed or intraperitoneally injected human transferrin prevents photoreceptor degeneration in rd10 mice. 2010

Emilie Picard, and Laurent Jonet, and Claire Sergeant, and Marie-Hélène Vesvres, and Francine Behar-Cohen, and Yves Courtois, and Jean-Claude Jeanny
Inserm, Paris, France. picardemilie@gmail.com

OBJECTIVE Retinal degeneration has been associated with iron accumulation in age-related macular degeneration (AMD), and in several rodent models that had one or several iron regulating protein impairments. We investigated the iron concentration and the protective role of human transferrin (hTf) in rd10 mice, a model of retinal degeneration. METHODS The proton-induced X-ray emission (PIXE) method was used to quantify iron in rd10 mice 2, 3, and 4 weeks after birth. We generated mice with the β-phosphodiesterase mutation and hTf expression by crossbreeding rd10 mice with TghTf mice (rd10/hTf mice). The photoreceptor loss and apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling in 3-week-old rd10/hTf mice and compared with 3-week-old rd10 mice. The neuroprotective effect of hTf was analyzed in 5-day-old rd10 mice treated by intraperitoneal administration with hTf for up to 25 days. The retinal hTf concentrations and the thickness of the outer nuclear layer were quantified in all treated mice at 25 days postnatally. RESULTS PIXE analysis demonstrated an age-dependent iron accumulation in the photoreceptors of rd10 mice. The rd10/hTf mice had the rd10 mutation, expressed high levels of hTf, and showed a significant decrease in photoreceptor death. In addition, rd10 mice intraperitoneally treated with hTf resulted in the retinal presence of hTf and a dose-dependent reduction in photoreceptor degeneration. CONCLUSIONS Our results suggest that iron accumulation in the retinas of rd10 mutant mice is associated with photoreceptor degeneration. For the first time, the enhanced survival of cones and rods in the retina of this model has been demonstrated through overexpression or systemic administration of hTf. This study highlights the therapeutic potential of Tf to inhibit iron-induced photoreceptor cell death observed in degenerative diseases such as retinitis pigmentosa and age-related macular degeneration.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D007501 Iron A metallic element with atomic symbol Fe, atomic number 26, and atomic weight 55.85. It is an essential constituent of HEMOGLOBINS; CYTOCHROMES; and IRON-BINDING PROTEINS. It plays a role in cellular redox reactions and in the transport of OXYGEN. Iron-56,Iron 56
D012160 Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the OPTIC NERVE and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the CHOROID and the inner surface with the VITREOUS BODY. The outer-most layer is pigmented, whereas the inner nine layers are transparent. Ora Serrata
D012162 Retinal Degeneration A retrogressive pathological change in the retina, focal or generalized, caused by genetic defects, inflammation, trauma, vascular disease, or aging. Degeneration affecting predominantly the macula lutea of the retina is MACULAR DEGENERATION. (Newell, Ophthalmology: Principles and Concepts, 7th ed, p304) Degeneration, Retinal,Degenerations, Retinal,Retinal Degenerations
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004577 Electron Probe Microanalysis Identification and measurement of ELEMENTS and their location based on the fact that X-RAYS emitted by an element excited by an electron beam have a wavelength characteristic of that element and an intensity related to its concentration. It is performed with an electron microscope fitted with an x-ray spectrometer, in scanning or transmission mode. Microscopy, Electron, X-Ray Microanalysis,Spectrometry, X-Ray Emission, Electron Microscopic,Spectrometry, X-Ray Emission, Electron Probe,X-Ray Emission Spectrometry, Electron Microscopic,X-Ray Emission Spectrometry, Electron Probe,X-Ray Microanalysis, Electron Microscopic,X-Ray Microanalysis, Electron Probe,Microanalysis, Electron Probe,Spectrometry, X Ray Emission, Electron Microscopic,Spectrometry, X Ray Emission, Electron Probe,X Ray Emission Spectrometry, Electron Microscopic,X Ray Emission Spectrometry, Electron Probe,X-Ray Microanalysis,Electron Probe Microanalyses,Microanalyses, Electron Probe,Microanalysis, X-Ray,Probe Microanalyses, Electron,Probe Microanalysis, Electron,X Ray Microanalysis,X Ray Microanalysis, Electron Microscopic,X Ray Microanalysis, Electron Probe
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D013052 Spectrometry, X-Ray Emission The spectrometric analysis of fluorescent X-RAYS, i.e. X-rays emitted after bombarding matter with high energy particles such as PROTONS; ELECTRONS; or higher energy X-rays. Identification of ELEMENTS by this technique is based on the specific type of X-rays that are emitted which are characteristic of the specific elements in the material being analyzed. The characteristic X-rays are distinguished and/or quantified by either wavelength dispersive or energy dispersive methods. Particle-Induced X-Ray Emission Spectrometry,Proton-Induced X-Ray Emission Spectrometry,Spectrometry, Particle-Induced X-Ray Emission,Spectrometry, Proton-Induced X-Ray Emission,Spectrometry, X-Ray Fluorescence,X-Ray Emission Spectrometry,X-Ray Emission Spectroscopy,X-Ray Fluorescence Spectrometry,Energy Dispersive X-Ray Fluorescence Spectrometry,Energy Dispersive X-Ray Fluorescence Spectroscopy,Energy Dispersive X-Ray Spectrometry,Energy Dispersive X-Ray Spectroscopy,Particle Induced X Ray Emission Spectrometry,Proton Induced X Ray Emission Spectrometry,Spectrometry, Particle Induced X Ray Emission,Spectrometry, Proton Induced X Ray Emission,Spectrometry, Xray Emission,Wavelength Dispersive X-Ray Fluorescence Spectrometry,Wavelength Dispersive X-Ray Fluorescence Spectroscopy,Wavelength Dispersive X-Ray Spectrometry,Wavelength Dispersive X-Ray Spectroscopy,X-Ray Fluorescence Spectroscopy,Xray Emission Spectroscopy,Emission Spectrometry, X-Ray,Emission Spectrometry, Xray,Emission Spectroscopy, X-Ray,Emission Spectroscopy, Xray,Energy Dispersive X Ray Fluorescence Spectrometry,Energy Dispersive X Ray Fluorescence Spectroscopy,Energy Dispersive X Ray Spectrometry,Energy Dispersive X Ray Spectroscopy,Fluorescence Spectrometry, X-Ray,Fluorescence Spectroscopy, X-Ray,Spectrometry, X Ray Emission,Spectrometry, X Ray Fluorescence,Spectroscopy, X-Ray Emission,Spectroscopy, X-Ray Fluorescence,Spectroscopy, Xray Emission,Wavelength Dispersive X Ray Fluorescence Spectrometry,Wavelength Dispersive X Ray Fluorescence Spectroscopy,Wavelength Dispersive X Ray Spectrometry,Wavelength Dispersive X Ray Spectroscopy,X Ray Emission Spectrometry,X Ray Emission Spectroscopy,X Ray Fluorescence Spectrometry,X Ray Fluorescence Spectroscopy,X-Ray Fluorescence Spectroscopies,Xray Emission Spectrometry

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