Therapeutic Action of the Mitochondria-Targeted Antioxidant SkQ1 on Retinopathy in OXYS Rats Linked with Improvement of VEGF and PEDF Gene Expression

Anton M Markovets,Natalia G Kolosova,Anzhella Z Fursova,Karl-Wilhelm Koch

doi:10.1371/journal.pone.0021682

Anton M Markovets, Natalia G Kolosova + Show 2 more

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https://doi.org/10.1371/journal.pone.0021682

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Abstract

The incidence of age-related macular degeneration (AMD), the main cause of blindness in older patients in the developed countries, is increasing with the ageing population. At present there is no effective treatment for the prevailing geographic atrophy, dry AMD, whereas antiangiogenic therapies successful used in managing the wet form of AMD. Recently we showed that mitochondria-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1) is able to prevent the development and moreover caused regression of pre-existing signs of the retinopathy in OXYS rats, an animal model of AMD. Here we examine the effects of SkQ1 on expression of key regulators of angiogenesis vascular endothelial growth factor A (VEGF) and its antagonist pigment epithelium-derived factor (PEDF) genes in the retina of OXYS rats as evidenced by real-time PCR and an ELISA test for VEGF using Wistar rats as control. Ophthalmoscopic examinations confirmed that SkQ1 supplementation (from 1.5 to 3 months of age, 250 nmol/kg) prevented development while eye drops SkQ1 (250 nM, from 9 to 12 months) caused some reduction of retinopathy signs in OXYS rats and did not reveal any negative effects on the control Wistar rat's retina. Prevention of premature retinopathy by SkQ1 was connected with an increase of VEGF mRNA and protein in OXYS rat's retina up to the levels corresponding to the Wistar rats, and did not involve changes in PEDF expression. In contrast the treatment with SkQ1 drops caused a decrease of VEGF mRNA and protein levels and an increase in the PEDF mRNA level in the middle-aged OXYS rats, but in Wistar rats the changes of gene expression were the opposite. Conclusions: The beneficial effects of SkQ1 on retinopathy connected with normalization of expression of VEGF and PEDF in the retina of OXYS rats and depended on age of the animals and the stage of retinopathy.

Highlights

Age-related macular degeneration is the most important cause of impaired vision and blindness in the aging population
Sixty percent of eyes in the control group (Fig. 2) presented with changes corresponding to the age-related macular degeneration (AMD) predisciform stage (1 a.u.), 5% corresponding to disciform stage (2 a.u.), and 35% did not have the signs of retinopathy
90% of eyes had changes corresponding to the predisciform stage (1 a.u.), 7% corresponding to the disciform stage (2 a.u.), and 3% of rats did not have the signs of retinopathy

Summary

Introduction

Age-related macular degeneration is the most important cause of impaired vision and blindness in the aging population. Animal research as well as observational studies suggests that antioxidant supplementation can slow down aging of the eye and possibly provide some protection against AMD [1,2]. Randomized controlled trials show that antioxidant supplements do not prevent early AMD [3]. Correct assessment of antioxidant effects in humans is difficult because of many factors, e.g., the long life span, high cost of randomized controlled trials, ethical issues, and difficult-tocontrol variables such as quality of life and individual differences in nutrition and age-related health problems. We showed previously that the senescence-accelerated OXYS rat strain is a suitable model for studying the pathogenesis of AMD and for identifying the relevant therapeutic targets [5,6,7,8,9]

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