scholarly journals Potential Treatment of Retinal Diseases with Iron Chelators

2018 ◽  
Vol 11 (4) ◽  
pp. 112 ◽  
Author(s):  
Wanting Shu ◽  
Joshua Dunaief

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sangeeta Satish ◽  
Hannah Philipose ◽  
Mariana Aparecida Brunini Rosales ◽  
Magali Saint-Geniez

Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.


Author(s):  
Junhua Wang ◽  
Peter D. Westenskow ◽  
Mingliang Fang ◽  
Martin Friedlander ◽  
Gary Siuzdak

Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic ‘fingerprint’ of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all- trans -retinal and its toxic end-product N -retinyl- N -retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation. This article is part of the themed issue ‘Quantitative mass spectrometry’.


2021 ◽  
Author(s):  
Tadeusz J Kaczynski ◽  
Elizabeth D Au ◽  
Michael H Farkas

Nuclear retention is a mechanism whereby RNA transcripts are held in the nucleus to maintain a proper nuclear-to-cytoplasmic balance or as a stockpile for use in responding to stimuli. Many mechanisms are employed to determine whether transcripts are retained or exported to the cytoplasm, though the extent to which tissue- or cell-type, stressors, or disease pathogenesis affect this process remains unclear. As the most biochemically active tissue in the body, the retina must mitigate endogenous and exogenous stressors to maintain cell health and tissue function. Oxidative stress, believed to contribute to the pathogenesis, or progression, of age-related macular degeneration (AMD) and inherited retinal dystrophies (IRDs), is produced both internally from biochemical processes, as well as externally from environmental insult. To evaluate the effect of oxidative stress on transcript localization in the retinal pigment epithelium (RPE), we performed poly-A RNA sequencing on nuclear and cytoplasmic fractions from induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells exposed to hydrogen peroxide, as well as untreated controls. Under normal conditions, the number of mRNA transcripts retained in the nucleus exceeded that found in studies of other tissues. Further, the nuclear-to-cytoplasmic ratio of transcripts is altered following oxidative stress, as is the retention of genes associated with AMD, IRDs, and those important for RPE physiology. These results provide a retention catalog of all expressed mRNA in iPSC-RPE under normal conditions and after exposure to hydrogen peroxide, offering insight into one of the potential roles oxidative stress plays in the progression of visual disorders.


2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Janusz Blasiak ◽  
Goran Petrovski ◽  
Zoltán Veréb ◽  
Andrea Facskó ◽  
Kai Kaarniranta

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible loss of vision in the elderly in developed countries. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, and genetic factors. Oxidative stress and the production of reactive oxygen species (ROS) seem to play a pivotal role in AMD pathogenesis. It is known that the macula receives the highest blood flow of any tissue in the body when related to size, and anything that can reduce the rich blood supply can cause hypoxia, malfunction, or disease. Oxidative stress can affect both the lipid rich retinal outer segment structure and the light processing in the macula. The response to oxidative stress involves several cellular defense reactions, for example, increases in antioxidant production and proteolysis of damaged proteins. The imbalance between production of damaged cellular components and degradation leads to the accumulation of detrimental products, for example, intracellular lipofuscin and extracellular drusen. Autophagy is a central lysosomal clearance system that may play an important role in AMD development. There are many anatomical changes in retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris in response to chronic oxidative stress, hypoxia, and disturbed autophagy and these are estimated to be crucial components in the pathology of neovascular processes in AMD.


Author(s):  
В.В. Педдер ◽  
А.А. Голубицких ◽  
Р.Н. Голых ◽  
Е.В. Хрусталева ◽  
С.И. Постольник ◽  
...  

На сегодняшний день одной из лидирующих причин инвалидности по зрению является возрастная макулярная дегенерация сетчатки (ВМД). Заболевание характеризуется преимущественным поражением хориокапиллярного слоя, мембраны Бруха и пигментного эпителия сетчатки, с последующим вовлечением фоторецепторов. За последнее десятилетие отмечается существенный рост частоты возникновения данной патологии как в пожилом, так и в молодом возрасте. Различают сухую и влажную форму ВМД. Повреждающие факторы различной этиологии запускают каскад патогенетический реакций, которые приводят к необратимой потере центрального зрения. В патогенезе заболевания существенная роль принадлежит окислительному стрессу, вследствие нарушения баланса между окислительными и антиоксидантными системами, вызывающего нарушение целостности комплекса фоторецепторов и пигментного эпителия сетчатки. Нарушение микроциркуляции в наружных слоях сетчатки приводит к накоплению эндотоксинов. Лимфатическая система, как одна из важнейших саногенно-потентных функций организма, участвует в купировании эндотоксикоза у больных ВМД за счёт лимфатической сорбции токсинов непосредственно в тканях с помощью лимфатических капилляров заинтересованного лимфорегиона. Отсутствие достаточно эффективных методов лечения макулодистрофии сетчатки глаза, позволяющих повысить зрительную функцию и предотвратить прогрессирование слепоты у пациентов, стимулирует поиск методов, использующих комплексное воздействие на патологически изменённые ткани глаза. В статье представлено обоснование комбинированного озон/NO-ультразвукового метода в сочетании с фотохромным и лазерным излучениями и антиоксидантами в лечении макулодистрофии сетчатки, позволяющими воздействовать на сетчатку глаз, как через слизистую полостей носа, так и поверхностно через кожные покровы лица и шеи в заинтересованных областях проекций лимфатических узлов и интерстиция по ходу отводящих от зрительного анализатора лимфатических сосудов. Предложенный метод лечения больных с ВМД позволяет осуществлять комбинированное лечебное воздействие комплексом физических и физико-химических факторов на дистрофически изменённую сетчатку глаз для купирования патологического процесса. Today, age-related macular degeneration of the retina (AMD) is one of the leading causes of vision disability. The disease is characterized by a predominant lesion of the choriocapillary layer, Bruch's membrane and retinal pigment epithelium, followed by the involvement of photoreceptors. Over the past decade, there has been a significant increase in the incidence of this pathology both in old and young age. Distinguish between dry and wet form of AMD. Damaging factors of various etiologies trigger a cascade of pathogenetic reactions that lead to irreversible loss of central vision. In the pathogenesis of the disease, an essential role belongs to oxidative stress, due to an imbalance between oxidative and antioxidant systems, which causes a violation of the integrity of the complex of photoreceptors and retinal pigment epithelium. Violation of microcirculation in the outer layers of the retina leads to the accumulation of endotoxins. The lymphatic system, as one of the most important sanogenic-potential functions of the body, is involved in the relief of endotoxicosis in patients with AMD due to the lymphatic sorption of toxins directly in the tissues with the help of the lymphatic capillaries of the interested lymph region. The lack of sufficiently effective methods for treating macular degeneration of the retina, allowing to increase visual function and prevent the progression of blindness in patients, stimulates the search for methods that use a complex effect on pathologically altered eye tissues. The article presents the rationale for the combined ozone / NO-ultrasound method in combination with photochromic and laser radiation and antioxidants in the treatment of macular degeneration of the retina, allowing to influence the retina, both through the nasal mucosa and superficially through the skin of the face and neck in zainte -resolved areas of the projections of the lymph nodes and interstitium along the lymphatic vessels diverting from the visual analyzer. The proposed method of treating patients with AMD allows for a combined therapeutic effect of a complex of physical and physicochemical factors on the dystrophically altered retina to arrest the pathological process.


2019 ◽  
Vol 20 (19) ◽  
pp. 4807 ◽  
Author(s):  
Feng Su ◽  
Christine Spee ◽  
Eduardo Araujo ◽  
Eric Barron ◽  
Mo Wang ◽  
...  

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD. Oxidative stress plays a key role in the development of AMD. We generated a chimeric high-density lipoprotein (HDL), mimetic peptide named HM-10/10, with anti-oxidant properties and investigated its potential for the treatment of retinal disease using cell culture and animal models of RPE and photoreceptor (PR) degeneration. Treatment with HM-10/10 peptide prevented human fetal RPE cell death caused by tert-Butyl hydroperoxide (tBH)-induced oxidative stress and sodium iodate (NaIO3), which causes RPE atrophy and is a model of geographic atrophy in mice. We also show that HM-10/10 peptide ameliorated photoreceptor cell death and significantly improved retinal function in a mouse model of N-methyl-N-nitrosourea (MNU)-induced PR degeneration. Our results demonstrate that HM-10/10 protects RPE and retina from oxidant injury and can serve as a potential therapeutic agent for the treatment of retinal degeneration.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1548
Author(s):  
E Seul Kim ◽  
Min Sang Lee ◽  
Hayoung Jeong ◽  
Su Yeon Lim ◽  
Doha Kim ◽  
...  

The wet type of age-related macular degeneration (AMD) accompanies the subfoveal choroidal neovascularization (CNV) caused by the abnormal extension or remodeling of blood vessels to the macula and retinal pigment epithelium (RPE). Vascular endothelial growth factor (VEGF) is known to play a crucial role in the pathogenesis of the disease. In this study, we tried to repurpose an investigational anticancer drug, rivoceranib, which is a selective inhibitor of VEGF receptor-2 (VEGFR2), and evaluate the therapeutic potential of the drug for the treatment of wet-type AMD in a laser-induced CNV mouse model using microsphere-based sustained drug release formulations. The PLGA-based rivoceranib microsphere can carry out a sustained delivery of rivoceranib for 50 days. When administered intravitreally, the sustained microsphere formulation of rivoceranib effectively inhibited the formation of subfoveal neovascular lesions in mice.


Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 842
Author(s):  
Manas R. Biswal ◽  
Zhaoyao Wang ◽  
Ryan J. Paulson ◽  
Rukshana R. Uddin ◽  
Yao Tong ◽  
...  

Erythropoietin (EPO) plays an important role in erythropoiesis by its action in blocking apoptosis of progenitor cells and protects both photoreceptors and retinal ganglion cells from induced or inherited degeneration. A modified form of EPO, EPO-R76E has attenuated erythropoietic activity but is effective in inhibiting apoptosis, oxidative stress, and inflammation in several models of retinal degeneration. In this study, we used recombinant Adeno Associated Virus (AAV) to provide long-term sustained delivery of EPO-R76E and demonstrated its effects in a mouse model of dry-AMD in which retinal degeneration is induced by oxidative stress in the retinal pigment epithelial (RPE) cells. Experimental vector AAV-EPO-R76E and control vector AAV-GFP were packaged into serotype-1 (AAV1) to enable RPE selective expression. RPE oxidative stress-mediated retinal degeneration was induced by exon specific deletion of the protective enzyme MnSOD (encoded by Sod2) by cre/lox mechanism. Experimental mice received subretinal injection of AAV-EPO-R76E in the right eye and AAV-GFP in the left eye. Western blotting of RPE/choroid protein samples from AAV-EPO-R76E injected eyes showed RPE specific EPO expression. Retinal function was monitored by electroretinography (ERG). EPO-R76E over-expression in RPE delayed the retinal degeneration as measured by light microscopy in RPE specific Sod2 knockout mice. Delivery of EPO-R76E vector can be used as a tool to prevent retinal degeneration induced by RPE oxidative stress, which is implicated as a potential cause of Age-Related Macular Degeneration.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2951
Author(s):  
Deepthi S. Rajendran Nair ◽  
Danhong Zhu ◽  
Ruchi Sharma ◽  
Juan Carlos Martinez Camarillo ◽  
Kapil Bharti ◽  
...  

Retinal pigment epithelium (RPE) replacement therapy is evolving as a feasible approach to treat age-related macular degeneration (AMD). In many preclinical studies, RPE cells are transplanted as a cell suspension into immunosuppressed animal eyes and transplant effects have been monitored only short-term. We investigated the long-term effects of human Induced pluripotent stem-cell-derived RPE (iPSC-RPE) transplants in an immunodeficient Royal College of Surgeons (RCS) rat model, in which RPE dysfunction led to photoreceptor degeneration. iPSC-RPE cultured as a polarized monolayer on a nanoengineered ultrathin parylene C scaffold was transplanted into the subretinal space of 28-day-old immunodeficient RCS rat pups and evaluated after 1, 4, and 11 months. Assessment at early time points showed good iPSC-RPE survival. The transplants remained as a monolayer, expressed RPE-specific markers, performed phagocytic function, and contributed to vision preservation. At 11-months post-implantation, RPE survival was observed in only 50% of the eyes that were concomitant with vision preservation. Loss of RPE monolayer characteristics at the 11-month time point was associated with peri-membrane fibrosis, immune reaction through the activation of macrophages (CD 68 expression), and the transition of cell fate (expression of mesenchymal markers). The overall study outcome supports the therapeutic potential of RPE grafts despite the loss of some transplant benefits during long-term observations.


Eye ◽  
2021 ◽  
Author(s):  
Alison J. Clare ◽  
Jian Liu ◽  
David A. Copland ◽  
Sofia Theodoropoulou ◽  
Andrew D. Dick

AbstractAge-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.


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