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.
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.
Along with microangiopathy, one of the main causes of blindness in diabetic retinopathy consists of degeneration of retinal neurons. Electron microscopy and morphometric analysis were used to study structural changes in neurosensory cells, associative, and ganglion neurons in the retina in 30 while mongrel male rats with streptozotocin diabetes for two months and the effects of a new semisynthetic antioxidant 4-methyl-2,6-diisobornylphenol, a screened phenol, were evaluated. Destructive changes were found to affect the outer segments of neurosensory cells and ganglion neurons. The number density of neurosensory and ganglion cells decreased, and the proportion of these cells with pyknotic nuclei increased. 4-Methyl-2,6-diisobornylphenol had neuroprotective actions, preventing destructive changes to neurosensory cells and ganglion neurons.
BackgroundThere has been considerable interest in discovery of the genetic architecture of complex traits, particularly age-related neurodegenerative disorders. To predict disease risk and to understand its genetic basis in humans, it is necessary to study animal models. Our previous research on the accelerated-senescence OXYS strain has revealed two quantitative trait loci (QTLs) on rat chromosome 1 that are associated with early cataract and/or retinopathy as well as with behavioral abnormalities. Each locus was partially mapped within the introgressed segments in a certain congenic strain: WAG/OXYS-1.1 or WAG/OXYS-1.2. Retinal transcriptome profiling of 20-day-old congenic and OXYS rats by high-throughput RNA sequencing uncovered relevant candidate genes and pathways. Nonetheless, the question remained open whether the same genetic components simultaneously have effects on various manifestations of the accelerated-senescence phenotype in OXYS rats. The present study was designed to analyze the genes of susceptibility to early neurodegenerative processes taking place in the OXYS rat retina and brain and to assess their potential functional clustering. The study was based on the findings from recent publications (including mapping of quantitative trait loci) and on comparative phenotyping of congenic rat strains.ResultsThe backcrossing of Wistar Albino Glaxo (WAG) and OXYS strains to generate the congenics resulted in two congenic strains with high susceptibility to cataract and retinopathy but with no obvious signs of Alzheimer’s disease-like brain pathology that are specific for OXYS rats. Thus, the genes of susceptibility to brain neurodegeneration were not introgressed into the congenic strains or there is a strong effect of the genetic background on the disease phenotype. Moreover, the progression of retinopathy with age was relatively less severe in the WAG background compared to the OXYS background. A comparative analysis of previously defined QTLs and congenic segments led to identification of candidate genes with a suspected effect on brain neurodegeneration including the genes showing differential expression in the congenic strains.ConclusionOverall, our findings suggest that the cause of the cataract and the cause of retinopathy phenotypes in OXYS rats may be genetically linked to each other within the introgressed segments in the WAG/OXYS-1.1 and/or WAG/OXYS-1.2 congenic strains.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0461-7) contains supplementary material, which is available to authorized users.
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