Abstract
Purpose: :
Iron-associated oxidative injury may affect development, rate and extent of retinal degeneration. This may be particularly relevant for the collateral cone injury often observed in retinal degenerations caused by rod-specific mutations. The metalo-complex Zinc-Desferrioxamine (Zn/DFO) may help reduce such injury by modulating iron bioavailability through chelation of labile iron and the release of Zinc in areas of increased iron levels. The aim of the present study was to evaluate whether treatment with Zn/DFO can reduce retinal oxidative injury and promote cone survival in the rd10 mouse model of retinitis pigmentosa.
Methods: :
During the first 4.5 weeks of life, intraperitoneal injections of ZnDFO (2.5mg/kg) were performed three times per week in rd10 mice. Electrophysiological, biochemical and quantitative immunohistochemical techniques were used to assess the course and extent of retinal degeneration and degree of oxidative injury.
Results: :
Previously (ARVO 2007, Program# 3712), we demonstrated that treatment with the Zn/DFO complex markedly protects retinal function and structure in rd10 mice. The maximal protective effect was seen at 4.5 weeks of age. At this time point RT-PCR analysis showed significantly lower levels of superoxide-dismutase and catalase mRNAs in Zn/DFO-treated mice as compared with saline-treated controls (p<0.0005) whereas levels of glutathione peroxidase mRNA were similar in both groups. Treatment with Zn/DFO led to a significant decrease of TBARS (2022±128 versus 2538±171nmol/mg protein in control, p<0.05), indicating lower levels of lipid peroxidation. 1Hz and 16Hz flicker cone ERG amplitudes were significantly higher in Zn/DFO-treated mice (n=10) as compared with saline control (n=6): at the highest stimulus intensity mean (±SEM) 1Hz amplitudes were 80.9±11.5µV versus 50.8±10.1µV in saline-injected mice (p<0.01); mean 16Hz flicker amplitudes were 34.6±4.4µV versus 14.4±2.3µV (p<0.001). Quantification of Red/Green and Blue cones in retinal whole mounts showed enhanced cone survival in Zn/DFO-treated animals: mean of 61475±4072 R/G cones and 50982±3587 Blue cones per retina (n=8) versus 37242±2390 (n=6, p<0.05) and 38711±3021, (p<0.01) in saline-treated controls.
Conclusions: :
Intraperitoneal injections of Zn/DFO, presumably by modulation of iron bioavailability, decrease extent of retinal oxidative stress and affect mRNA levels of antioxidant enzymes in rd10 mice. This is associated with enhanced cone function and survival.
Keywords: oxidation/oxidative or free radical damage • antioxidants • retinal degenerations: cell biology