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A. Obolensky, R. Alper, E. Deleon, M. Lederman, E. Berenshtein, M. Chevion, I. Chowers, E. Banin; Zinc-Desferrioxamine Complex Delays Retinal Degeneration in rd10 Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3712.
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Recent studies suggest that iron-associated oxidative injury may play a role in retinal degenerations. The metalo-complex Zinc-Desferrioxamine (Zn/DFO) may ameliorate such injury by chelation of labile iron in combination with release of Zinc in areas of increased iron levels. Our aim was to evaluate whether treatment with Zn/DFO can reduce the rate and extent of retinal degeneration in the rd10 mouse model of retinitis pigmentosa.
During the first six weeks of life, intraperitoneal injections of ZnDFO (2.5mg/kg) were performed three times per week in rd10 mice. Three control groups were similarly injected with either saline, ZnCl2, or desferrioxamine (DFO) alone in concentrations equivalent to their content in the Zn/DFO complex. At 3, 4.5 and 6 weeks of age electrophysiologic (full field electroretinogram - ERG), and quantitative histologic as well as immunohistochemical techniques were used to assess the course and extent of retinal degeneration.
At 3 weeks of age amplitudes of dark-adapted ERG mixed cone-rod responses and flicker ERG were already reduced in both Zn/DFO-treated and control-treated rd10 mice as compared to C57/Bl6 wild-type mice. However, Zn/DFO treated animals showed significantly higher amplitudes than controls at both the 3 and 4.5 week time points (mean b-wave amplitude at highest stimulus intensity at 3 weeks: 402.8±53.2µV versus 251.3±35.1µV in saline-injected mice, p<0.05; at 4.5 weeks, 174.0±19.9µV versus 110.6±19.1µV, p<0.05). A partial rescue effect of Zn and DFO alone was present at 4.5 weeks of age, but not at 3 weeks. At 6 weeks, ERG was unrecordable in all experimental groups. Morphometric analysis showed corresponding structural rescue: at 4.5 weeks of age, the outer nuclear layer in the peripheral retina was significantly thicker in Zn/DFO-treated mice than in controls (8.31±0.46µm versus 6.45±0.55µm in saline-injected animals, p<0.01). At 3 and 4.5 weeks of age, quantitative immunohistochemistrty showed a trend towards larger rhodopsin content in Zn/DFO-treated animals as compared with control-treated mice.
Intraperitoneal injections of Zn/DFO provide significant functional and structural retinal protection in rd10 mice. We speculate that this rescue effect of the Zn/DFO complex is related to its ability to reduce formation of reactive oxygen species by modulation of iron availability.
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