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. 2011;6(7):e21682.
doi: 10.1371/journal.pone.0021682. Epub 2011 Jul 5.

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

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Free PMC article

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 et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Distribution of OXYS rat eyes by stage of retinopathy.
Supplementation with 250 nmol SkQ1/kg per day starting at age 1.5 months prevents the development of retinopathy in OXYS rats. “a.u.” are arbitrary units for estimation of degree of retinopathy (explained in Materials and Methods).
Figure 2
Figure 2. Distribution of OXYS rat eyes by stage of retinopathy.
SkQ1 eye drops inhibit the development of retinopathy in OXYS rats, averaged data. “a.u.” are arbitrary units for estimation of degree of retinopathy (explained in Materials and Methods).
Figure 3
Figure 3. Effects of SkQ1 supplementation (250 nmol per kg of body weight per day) from age 1.5 to 3 months on (a) messenger RNA (mRNA) expression (N = 7) and (b) the protein level (N = 4) of vascular endothelial growth factor (VEGF) in rat retina.
Data are presented as mean±SEM (standard error of the mean). * - in comparison with control; ∧ - in comparison with Wistar rats.
Figure 4
Figure 4. Effects of SkQ1 on retinal level of mRNA of pigment epithelium-derived factor (PEDF), N = 8–10.
Data are presented as mean±SEM. (a) SkQ1 supplementation, 250 nmol per kg of body weight per day from 1.5 to 3 months of age; (b) SkQ1 eye drops (250 nM, one drop per day) from age 9 to 12 months. * - in comparison with control, p<0.05; ∧ - in comparison with Wistar rats.
Figure 5
Figure 5. Effects of SkQ1 eye drops (from 9 to 12 months of age) on (a) mRNA expression (N = 8–10) and (b) protein level (N = 4) of vascular endothelial growth factor (VEGF) in rat retina.
Data are presented as mean±SEM. * - in comparison with control; ∧ - in comparison with Wistar rats.
Figure 6
Figure 6. Fundus photograph of rat retina (a) Normal fundus from 12-months-old Wistar rat.
Ratio of blood vessels is normal. The retina between vascular arcades is not damaged (changed). (b) Geographic atrophy of retinal pigment epithelium of retina from 3-months-old OXYS rats. Obliteration of choroidal vessels, obliteration and sclerosis of retina vessels. Redistribution of pigmentation. (c) Fundus photograph from 12-months-old OXYS rat. Confluent soft drusen-like deposits, retinal pigment epithelium detachment, latent choroidal neovascularization on optic disc.

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