The Mitochondria-Targeted Antioxidant SkQ1 Downregulates Aryl Hydrocarbon Receptor-Dependent Genes in the Retina of OXYS Rats with AMD-Like Retinopathy.

M L Perepechaeva,A Yu Grishanova,N G Kolosova,E A Rudnitskaya

doi:10.1155/2014/530943

Abstract

The mitochondria-targeted antioxidant SkQ1 is a novel drug thought to retard development of age-related diseases. It has been shown that SkQ1 reduces clinical signs of retinopathy in senescence-accelerated OXYS rats, which are a known animal model of human age-related macular degeneration (AMD). The aim of this work was to test whether SkQ1 affects transcriptional activity of AhR (aryl hydrocarbon receptor) and Nrf2 (nuclear factor erythroid 2-related factor 2), which are considered as AMD-associated genes in the retina of OXYS and Wistar rats. Our results showed that only AhR and AhR-dependent genes were sensitive to SkQ1. Dietary supplementation with SkQ1 decreased the AhR mRNA level in both OXYS and Wistar rats. At baseline, the retinal Cyp1a1 mRNA level was lower in OXYS rats. SkQ1 supplementation decreased the Cyp1a1 mRNA level in Wistar rats, but this level remained unchanged in OXYS rats. Baseline Cyp1a2 and Cyp1b1 mRNA expression was stronger in OXYS than in Wistar rats. In the OXYS strain, Cyp1a2 and Cyp1b1 mRNA levels decreased as a result of SkQ1 supplementation. These data suggest that the Cyp1a2 and Cyp1b1 enzymes are involved in the pathogenesis of AMD-like retinopathy of OXYS rats and are possible therapeutic targets of SkQ1.

Highlights

Mitochondria-targeted antioxidant SkQ1 (cationic plastoquinone derivative (10-[6󸀠-plastoquinonyl] decyltriphenylphosphonium) is a novel medication that is designed to retard the development of age-related diseases and aging [1, 2]
TRI-Reagent and RNA Secure Reagent were purchased from Ambion (USA); the cDNA synthesis MMLV RT kit and PCR kit qPCRmix-HS were from Evrogen (Russia); RNasin and RQ1 DNase were from Promega (USA); oligonucleotides for analysis of the rat genes Cyp1a1, Cyp1a2, Cyp1b1, Gsta1, NAD(P)H: quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenase 3A1 (Aldh3a1), Ugt1a6, Ugt1a9, aryl hydrocarbon receptor (AhR), nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione S-reductase (Gsr), thioredoxin reductase 1 (Txnrd1), heme oxygenase 1 (Hmox1), and Gapdh were from Syntol (Russia)
Our data show that the genotype had no influence on the AhR mRNA level (Figure 1(a)) in the retina (F1,22 = 1.02, P = 0.32), but this parameter was affected by SkQ1 (F1,22 = 16.00, P = 0.0007)

Summary

Introduction

Mitochondria-targeted antioxidant SkQ1 (cationic plastoquinone derivative (10-[6󸀠-plastoquinonyl] decyltriphenylphosphonium) is a novel medication that is designed to retard the development of age-related diseases and aging [1, 2]. The effects of SkQ1 on aging are accompanied by inhibition of development of such age-related problems as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, and peroxidation of lipids and proteins [1, 3]. It was shown that addition of SkQ1 to food or treatment with SkQ1 eye drops prevents development of retinopathy and reduces severity of preexisting pathological changes in the retina of senescenceaccelerated OXYS rats [6]. OXYS rats develop a retinopathy similar to the dry form of human AMD judging by the symptoms, morphology, and some molecular changes. It was reported that the effects of SkQ1 include improvement of functions of the retinal pigment epithelium and a reduction of lipofuscin accumulation

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