[Leukocyte telomere length and response to antiangiogenic therapy in patients with neovascular age-related macular degeneration.]

Age-related macular degeneration (AMD) is becoming the leading cause of vision loss in people over 60 years of age. The neovascular form of AMD (nVMD) is characterized by choroidal neovascularization (CNV), the main trigger of which is vascular endothelial growth factor (VEGF), the inhibition of which is the current standard of treatment. Significant variability of response to anti-VEGF therapy determines the relevance of the search for biological markers - prognostic criteria of treatment response. We analyzed the response of 110 nVMD patients to anti-VEGF therapy depending on the functional and anatomical parameters of the retina (according to optical coherence tomography, OCT) and leukocyte telomere length (LTL, was assessed by quantitative PCR). Positive dynamics of best corrected visual acuity (BCVA) was observed in 100% of eyes. The central retinal thickness (CRT) decreased after the 3rd injection to 265 [234-306] µm, by the end of the observation period - to 211 [190-262] µm. The retention of activity of the subretinal neovascular membrane (SNM) at the end of the observation period correlated with lower values of the initial BCVA and high values of the initial CRT. An association of LTL with response to treatment was revealed: in patients with higher LTL the active form of SNM was more often switched to inactive after three injections, while with lower LTL, the activity of SNM was more often preserved, which determined the need for more intravitreal injections.

Autophagy as a Target for the Retinoprotective Effects of the Mitochondria-Targeted Antioxidant SkQ1.

Age-related macular degeneration (AMD) is a complex neurodegenerative disease, a main cause of vision loss in elderly people. The pathogenesis of dry AMD, the most common form of AMD (~ 80% cases), involves degenerative changes in the retinal pigment epithelium (RPE), which are closely associated with the age-associated impairments in autophagy. Reversion of these degenerative changes is considered as a promising approach for the treatment of this incurable disease. The purpose of our study was to assess the relationship between previously identified retinoprotective effects of the mitochondrial antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1) and its influence on the autophagy process in senescence-accelerated OXYS rats characterized by the development of AMD-like retinopathy (Wistar rats were used as a control). The treatment with SkQ1 (250 nmol/kg body weight) during the period of active disease progression (from 12 to 18 months of age) completely prevented progression of clinical manifestations of retinopathy in the OXYS rats, suppressed atrophic changes in the RPE cells and activated autophagy in the retina, which was evidenced by a significant decrease in the content of the multifunctional adapter protein p62/Sqstm1 and increase in the level of the Beclin1 gene mRNA. In general, the results obtained earlier and in the present study have shown that SkQ1 is a promising agent for prevention and suppression of AMD.

VEGF and PEDF levels in the rat retina: effects of aging and AMD-like retinopathy.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. By clinical signs, there are two forms of AMD: the atrophic or dry (~ 90% of all cases) and wet or neovascular AMD (~10% of cases). Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet AMD. However, there are emerging signals that anti-VEGF treatment can potentially increase development of atrophic AMD. There is neither a treatment of the dry AMD due poor understanding of the pathogenesis and retina aging process in general. We have shown previously that senescence-accelerated OXYS rats are a suitable model of dry AMD. Signs of retinopathy in OXYS rats manifest themselves by age 3 months against the background of a decline in the number of retinal pigment epithelium (RPE) cells and an alteration of choroidal microcirculation. Herein, we compared retinal expression of proteins VEGF and PEDF (pigment epithelium-derived factor) between OXYS and Wistar rats (control). The amount of the VEGF protein increased with age in the retina of both rat strains from 3 months of age. From age 3 to 24 months, this parameter was significantly lower in OXYS rats than in Wistar rats. PEDF protein concentration was significant lower in the OXYS retina only at the age of 3 months. We can conclude that development of retinopathy in OXYS rats takes place at reduced concentrations of VEGF and PEDF. Because RPE cells control the VEGF-PEDF balance, an RPE-targeted approach is a logical choice for AMD treatment and for decreasing adverse effects of anti-VEGF treatment.

Changes in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration.

Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in people over 60 years old. The major role in AMD pathogenesis belongs to structure-functional changes in the retinal pigment epithelium cells, while the onset and progression of AMD are commonly believed to be caused by the immune system dysfunctions. The role of retinal glial cells (Muller cells, astrocytes, and microglia) in AMD pathogenesis is studied much less. These cells maintain neurons and retinal vessels through the synthesis of neurotrophic and angiogenic factors, as well as perform supporting, separating, trophic, secretory, and immune functions. It is known that retinal glia experiences morphological and functional changes with age. Age-related impairments in the functional activity of glial cells are closely related to the changes in the expression of trophic factors that affect the status of all cell types in the retina. In this review, we summarized available literature data on the role of retinal macro- and microglia and on the contribution of these cells to AMD pathogenesis.

[Molecular mechanisms of cell death in the retina during the development of age-related macular degeneration].

Age-related macular degeneration (AMD) is a chronic progressive disease characterized by lesions in the central area of the retina. The pathogenesis of AMD involves aging-associated changes in the choriocapillaris, retinal pigment epithelium (RPE), and in Bruch's membrane, but the mechanisms that trigger the conversion of normal age-related changes into the pathological process are not known. The result of pathological changes in the RPE and choroid is the death of photoreceptors and irreversible loss of vision. In spite of numerous studies on AMD pathogenesis, the information about the molecular genetic preconditions of events leading to the death of photoreceptors - as well as about the pathways of death - is extremely limited. This situation makes it difficult to identify effective treatments of AMD, in particular, the most common, i.e., atrophic («dry¼) form of the disease. Recent studies showed that not only proapoptotic but also necrosis-associated, and autophagy-related signaling pathways are involved in the death of retinal cells. This review summarizes the data available in the literature on the three basic types of cell death: apoptosis, necrosis, and autophagy and their role in the pathogenesis of AMD.

[Expression of nitric oxide synthases in the retina of OXYS rats during retinopathy development].

Both the lack and excess generation of nitric oxide (NO) contributes to the pathogenesis of age-related diseases, according to the latest data including age-related macular degeneration (AMD), which is a leading cause of vision loss in people over 65. The mechanisms of the effects of NO are not entirely clear, the information about changes in the expression synthase NO (NOSs) in the retina with age and the development of AMD are limited. We showed previously that the senescence-accelerated OXYS rats strain is an animal model of AMD. The purpose of the present research was to compare the transcriptional activity of genes NOSs: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS) in the retina OXYS and Wistar rats (used as control) by real-time PCR. The study was carried out on animals at the age of 3 and 18 months during the period of manifestation and active progression of AMD-like retinopathy in OXYS rats. We showed that mRNA level of NOSs was not dependent on age in Wistar and OXYS rats. Interstrain differences in the level of eNOS mRNA were not detected, but the level of mRNA of nNOS in the retina of 18-month-old OXYS rats was 2,4 times higher than in age-matched Wistar rats. Regardless of age the level of iNOS mRNA in OXYS rats was 7 times lower than that in Wistar rats, but the protein content of iNOS in 3-month-old OXYS rats (ELISA data) was increased. Perhaps such a paradoxical situation reflects a decreased reactivity of the immune system in the OXYS rats.