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

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.

The mitochondria-targeted antioxidant SkQ1 restoresαB-crystallin expression and protects against AMD-like retinopathy in OXYS rats

“…In the present study, in support of our previous reports, [10][11]21 we demonstrated that dietary supplementation with the mitochondria-targeted antioxidant SkQ1 is effective at suppressing the development of retinopathy in OXYS rats. Here we for the first time showed that the therapeutic action of SkQ1 involves restoration (increase) of expression of a small heat shock protein, aB-crystallin, in the retina of OXYS rats.…”

“…35 It is thought that the accelerated senescence and development of age-related diseases in OXYS rats is also linked with progressive mitochondrial dysfunction. 21,23,36 Thus, we can hypothesize that SkQ1 protects against stress and restores mitochondrial function in the retina of OXYS rats. In RPE cells, aB-crystallin provides critical protection of mitochondrial function, which prevents ER stress-mediated apoptosis.…”

“…Indeed, supplementation with SkQ1 restored the levels of VEGF gene expression in the retina of OXYS rats without neovascularization. 21 There is a growing body of evidence in support of an association of mitochondrial dysfunction with retinal degenerative diseases including AMD. 35 It is thought that the accelerated senescence and development of age-related diseases in OXYS rats is also linked with progressive mitochondrial dysfunction.…”

“…[9][10][11][12] It was also shown that SkQ1 has a therapeutic potential against other agerelated diseases 9,[13][14][15][16][17] and increases the lifespan. 18,19 It is believed that the development of retinopathy in OXYS rats, just like AMD in humans, is associated with progressive mitochondrial dysfunction 20,21 and with accumulation of b-amyloid. 22 Recently, by means of high-throughput RNA sequencing (RNA-Seq), we determined that the retinopathy in OXYS rats develops simultaneously with a decrease in the mRNA level of hundreds of genes including aB-crystallin (Cryab).…”

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…At present, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which is characterized by early development of a phenotype similar to human geriatric disorders. This pathological phenotype primarily includes accelerated thymus involution, [28][29][30] retinopathy similar to human AMD, [31][32][33][34] high blood pressure, 35 and senile osteoporosis. 36-38 Accelerated brain aging manifests itself in OXYS rats as early development of behavioral and cognitive alterations against the background of neurodegenerative changes driven by an AD-like metabolic pathway.…”