Abstract
Purpose: :
Oxidative injury may contribute to cell death in retinal and macular degenerations associated with genetic defects. We aimed to assess whether such genetically-driven degenerative processes affect retinal susceptibility to exogenous oxidative challenges, and whether anti-oxidants modify this susceptibility.
Methods: :
Oxidative stress was induced in retinas of three-week-old C57BL/6 (WT) and rd10 mice by intravitreal injection of 2mM paraquat (PQ). A subgroup of rd10 mice was pre-treated by intraperitoneal injections of zinc-desferrioxamine (Zn/DFO) complexes, which provide anti-oxidant activity. Three days following PQ injection retinal function was evaluated by ERG, retinal structure by histology, and oxidative injury was quantified by 4-Hydroxy-2-nonenal (HNE) staining and by TBARS assay. Retinal anti-oxidative capability was assessed by quantitative PCR for anti-oxidant genes (Superoxide Dismutase1, Glutathione Peroxidase, Catalase) and by measurement of catalase activity.
Results: :
Following PQ injection, average ERG dark-adapted b-wave amplitudes in injected vs. sham treated eyes decreased by 76% in WT mice compared with 50% in rd10 mice (p=0.02). Altered retinal morphology associated with PQ was observed in WT but not in rd10 eyes. Oxidative injury, as measured by HNE staining and TBARS assay, increased significantly following PQ injection in both groups as compared to sham-injected fellow eyes (p<0.04). Yet, the magnitude of increase was higher in WT as compared with rd10 mice: HNE by 1.3-fold, TBARS by 2.1-fold. Pre-PQ injection, mRNA levels of anti-oxidant genes were 1.5-1.8-fold higher in rd10 compared with WT mice (p<0.01 for each gene). Catalase activity was 6.3 u/mg and 3.7 u/mg in rd10 and WT mice, respectively (p=0.0006). rd10 mice pre-treated with Zn/DFO had pre-PQ catalase activity and anti-oxidant mRNA status similar to that of WT mice. Yet, ERG demonstrated that Zn/DFO-treated rd10 mice still retained the relative resistance to PQ injection which characterizes untreated rd10 mice.
Conclusions: :
The degenerative process in rd10 mice may render the retina less susceptible to exogenous oxidative injury. Increased activity of anti-oxidative mechanisms may account for this relative protection. Zn/DFO treatment may attenuate retinal degeneration in rd10 mice (ARVO 2007, #3712), while at the same time preserving the increased threshold for exogenous oxidative challenge.
Keywords: oxidation/oxidative or free radical damage • antioxidants • retina