Pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the world, remains poorly understood. This makes it necessary to create animal models for studying AMD pathogenesis and to design new therapeutic approaches. Here we showed that retinopathy in OXYS rats is similar to human AMD according to clinical signs, morphology, and vascular endothelium growth factor (VEGF) and pigment epithelium-derived factor (PEDF) genes expression. Clinical signs of retinopathy OXYS rats manifest by the age 3 months against the background of significantly reduced expression level of VEGF and PEDF genes due to the decline of the amount of retinal pigment epithelium (RPE) cells and alteration of choroidal microcirculation. The disruption in OXYS rats' retina starts at the age of 20 days and appears as reduce the area of RPE cells but does not affect their ultrastructure. Ultrastructural pathological alterations of RPE as well as develop forms of retinopathy are observed in OXYS rats from age 12 months and manifested as excessive accumulation of lipofuscin in RPE regions adjacent to the rod cells, whirling extentions of the basement membrane into the cytoplasm. These data suggest that primary cellular degenerative alterations in the RPE cells secondarily lead to choriocapillaris atrophy and results in complete loss of photoreceptor cells in the OXYS rats' retina by the age of 24 months.

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Abbreviations: AMD, age-related macular degeneration; RPE, retinal pigment epithelium; SkQ1, 10-(6 0 plastoquinonyl)decyltriphenylphosphonium.Age-related macular degeneration (AMD), a neurodegenerative and vascular retinal disease, is the leading cause of blindness in the developed world. Accumulating evidence suggests that alterations in the expression of a small heat shock protein (aB-crystallin) are involved in the pathogeneses of AMD. Here we demonstrate that senescenceaccelerated OXYS rats-an animal model of the dry form of AMD-develop spontaneous retinopathy against the background of reduced expression of aB-crystallin in the retina at the early preclinical stages of retinopathy (age 20 days) as well as at 4 and 24 months of age, during the progressive stage of the disease. The level of aA-crystallin expression in the retina of OXYS rats at all the ages examined was no different from that in disease-free Wistar rats. Treatment with the mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from 1.5 to 4 months of age, 250 nmol/kg, increased the level of aB-crystallin expression in the retina of OXYS rats. SkQ1 slowed the development of retinopathy and reduced histological aberrations in retinal pigment epithelium cells. SkQ1 also attenuated neurodegenerative changes in the photoreceptors and facilitated circulation in choroid blood vessels in the retina of OXYS rats; this improvement was probably linked with the restoration of aB-crystallin expression.

OXYS rats are characterized by early development of cataract and chorioretinal degeneration with clinical manifestations similar to those observed in senile cataract and age-associated macular degeneration in humans. According to fundoscopy findings, the incidence of chorioretinal degeneration sharply increases in OXYS rats by the age of 4.5 months, when all animals develop signs of fundus oculi pathology. Morphological analysis of semithin sections of the posterior wall of the eye in OXYS rats aged 5 months showed that choroid vessels, pigmented epithelium, and radial glia were most vulnerable to injury. Retinal hypoxia and destruction of the pigmented epithelium associated with circulatory disorders in the choroid vessels presumably lead to injuries of the neurosensory cells (mainly the external segments) and a 3.5-fold increase in the percent of photoreceptors with nuclear pyknosis in comparison with the control. These results indicate that OXYS rats represent an adequate model of age-associated macular degeneration and can be used for studies of the pathogenesis of this condition and development of methods for its treatment and prevention.