scholarly journals Iron is neurotoxic in retinal detachment and transferrin confers neuroprotection

2019 ◽  
Vol 5 (1) ◽  
pp. eaau9940 ◽  
Author(s):  
Alejandra Daruich ◽  
Quentin Le Rouzic ◽  
Laurent Jonet ◽  
Marie-Christine Naud ◽  
Laura Kowalczuk ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Vision Loss ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Subretinal Fluid ◽  
Predictive Marker ◽  
Visual Recovery ◽  
Neuroprotective Effects

In retinal detachment (RD), photoreceptor death and permanent vision loss are caused by neurosensory retina separating from the retinal pigment epithelium because of subretinal fluid (SRF), and successful surgical reattachment is not predictive of total visual recovery. As retinal iron overload exacerbates cell death in retinal diseases, we assessed iron as a predictive marker and therapeutic target for RD. In the vitreous and SRF from patients with RD, we measured increased iron and transferrin (TF) saturation that is correlated with poor visual recovery. In ex vivo and in vivo RD models, iron induces immediate necrosis and delayed apoptosis. We demonstrate that TF decreases both apoptosis and necroptosis induced by RD, and using RNA sequencing, pathways mediating the neuroprotective effects of TF are identified. Since toxic iron accumulates in RD, we propose TF supplementation as an adjunctive therapy to surgery for improving the visual outcomes of patients with RD.

scholarly journals Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1095
Author(s):  
Marianne Berdugo ◽  
Kimberley Delaunay ◽  
Cécile Lebon ◽  
Marie-Christine Naud ◽  
Lolita Radet ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Oral Treatment ◽  
Retinal Pigment ◽  
Retinal Function ◽  
Acute Administration ◽  
One Year

Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

scholarly journals Ocular Toxoplasmosis: Mechanisms of Retinal Infection and Experimental Models

Parasitologia ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 50-60
Author(s):  
Veronica Rodriguez Fernandez ◽  
Giovanni Casini ◽  
Fabrizio Bruschi
Keyword(s):  
Ex Vivo ◽  
Cell Damage ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Ocular Toxoplasmosis ◽  
Cell Infection

Ocular toxoplasmosis (OT) is caused by the parasite Toxoplasma gondii and affects many individuals throughout the world. Infection may occur through congenital or acquired routes. The parasites enter the blood circulation and reach both the retina and the retinal pigment epithelium, where they may cause cell damage and cell death. Different routes of access are used by T. gondii to reach the retina through the retinal endothelium: by transmission inside leukocytes, as free parasites through a paracellular route, or after endothelial cell infection. A main feature of OT is the induction of an important inflammatory state, and the course of infection has been shown to be influenced by the host immunogenetics. On the other hand, there is evidence that the T. gondii phenotype also has an impact on the distribution of the pathology in different areas. Although considerable knowledge has been acquired on OT, a deeper knowledge of its mechanisms is necessary to provide new, more targeted treatment strategies. In particular, in addition to in vitro and in vivo experimental models, organotypic, ex vivo retinal explants may be useful in this direction.

scholarly journals Inhibition of mitochondrial fission preserves photoreceptors after retinal detachment

2017 ◽  
Author(s):  
Xiangjun She ◽  
Xinmin Lu ◽  
Tong Li ◽  
Junran Sun ◽  
Jian Liang ◽  
...  
Keyword(s):  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Photoreceptor Degeneration ◽  
Apoptotic Pathway ◽  
Neurosensory Retina

AbstractPhotoreceptor degeneration is a leading cause of visual impairment worldwide. Separation of neurosensory retina from the underlying retinal pigment epithelium is a prominent feature preceding photoreceptor degeneration in a variety of retinal diseases. Although ophthalmic surgeries have been well developed to restore retinal structures, post-op patients usually experience progressive photoreceptor degeneration and irreversible vision loss that is incurable at present. Previous studies point to a critical role of mitochondria-mediated apoptotic pathway in photoreceptor degeneration, but the upstream triggers remain largely unexplored. In this study, we show that after experimental RD induction, photoreceptors activate dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway and subsequent apoptotic cascades. Mechanistically, endogenous ROS is necessary for Drp1 activation in vivo and exogenous ROS insult is sufficient to activate Drp1-dependent mitochondrial fission in cultured photoreceptors. Accordingly, inhibition of Drp1 activity effectively preserves mitochondrial integrity and rescues photoreceptors. Collectively, our data delineates a ROS-Drp1-mitochondria axis that promotes photoreceptor degeneration in retinal diseased models.

scholarly journals Spontaneous Closure of the Macular Hole in a Patient with Acquired Vitelliform Lesion

2020 ◽  
Vol 11 (1) ◽  
pp. 16-21
Author(s):  
Masanori Fukumoto ◽  
Shou Oosuka ◽  
Takaki Sato ◽  
Teruyo Kida ◽  
Tsunehiko Ikeda
Keyword(s):  
Retinal Detachment ◽  
Macular Hole ◽  
Rare Case ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Serous Retinal Detachment ◽  
Subretinal Fluid ◽  
Spontaneous Closure ◽  
Retinal Reattachment

In this paper, we report an extremely rare case of spontaneous closure of a macular hole (MH) that developed in a patient in whom acquired vitelliform lesion (AVL) occurred after vitrectomy for atopic retinal detachment (ARD). A 32-year-old male developed ARD in both eyes, and retinal reattachment was achieved after vitrectomy. Five years after surgery, optical coherence tomography showed localized serous retinal detachment (SRD) and a granular lesion with a higher brightness in the subretinal fluid, thus leading to the diagnosis of AVL. One month later, an MH developed, and a follow-up examination performed 6 weeks later revealed that the MH had spontaneously closed and the SRD decreased. In the fovea, fluorescein angiography revealed a window defect due to atrophy of the retinal pigment epithelium (RPE). These findings in this present case suggest the possibility that RPE dysfunction was involved in the development of AVL and MH.

scholarly journals Acute exudative polymorphous vitelliform maculopathy during pembrolizumab treatment for metastatic melanoma: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ine Lambert ◽  
Giuseppe Fasolino ◽  
Gil Awada ◽  
Robert Kuijpers ◽  
Marcel ten Tusscher ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Checkpoint Inhibitors ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Anterior Segment ◽  
Subretinal Fluid ◽  
Additional Treatment ◽  
Central Visual Field ◽  
Immunomodulating Therapy ◽  
Neurosensory Retinal Detachment

Abstract Background The use of immunomodulating therapy to treat various cancers has been on the rise and these immune checkpoint inhibitors are known to cause ocular side effects. In this article a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) is reported which developed during a first line treatment with pembrolizumab. Case presentation A 54-year-old woman was referred because of blurry vision in both eyes with a yellow spot in the central visual field of the left eye. These symptoms started after four treatments with pembrolizumab (a monoclonal antibody against the programmed cell death receptor-1) for a metastatic recurrent vaginal mucosal melanoma. Her best corrected visual acuity was 10/10 in both eyes with a correction of + 2.00 bilaterally. There were no inflammatory findings in the anterior segment or the vitreous. Fundoscopy revealed an attenuation of the foveal reflex with subtle yellow-white subretinal macular deposits (vitelliform lesions) in both eyes. Fluorescein angiography did not show staining or leakage in the mid-phase, neither a late staining. Spectral-domain optical coherence tomography of the macula illustrated bilateral neurosensory retinal detachment with a thick, highly reflective band at the outer photoreceptor segment. En face structural OCT at the level of the photoreceptors showed focal areas of increased signal corresponding to hyperreflective vitelliform material. The treatment with pembrolizumab was ceased immediately. During the following visits we slowly saw an improvement of the neurosensory retinal detachment. After almost four months a total resolution of the subretinal fluid was visualized in both eyes without the use of additional treatment, though the vitelliform deposits persisted. Conclusions The development of AEPVM in melanoma patients could be triggered by treatment with Pembrolizumab. Pembrolizumab has the potential to disturb indirectly the retinal pigment epithelium homeostasis with accumulation of lipofuscin deposits and subretinal fluid, both signs of AEPVM.

scholarly journals Metabolic function in aging retina and retinal pigment epithelium remains robust despite vision loss

2021 ◽  
Author(s):  
Kristine A. Tsantilas ◽  
Whitney M. Cleghorn ◽  
Celia M. Bisbach ◽  
Jeremy A. Whitson ◽  
Daniel T. Hass ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Glucose Metabolism ◽  
Vision Loss ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Glutamine Metabolism ◽  
Gas Chromatography Mass Spectrometry ◽  
Metabolic Function ◽  
Age Related

AbstractPurposeCharacterize how metabolic function in the murine retina and retinal pigment epithelium-choroid-sclera (eyecup) complex is impacted by natural aging.MethodsWe examined scotopic and photopic visual function of young (3-6 months) and aged (23-26 months) C57Bl/6J mice using electroretinograms (ERGs). Metabolic changes in retina and eyecup explants were characterized by measuring uptake and usage of U-13C-glucose or U-13C-glutamine at different timepoints by gas chromatography-mass spectrometry (GC-MS), measuring oxygen consumption rate (OCR) using a perifusion apparatus, and determining ATP levels with a bioluminescence assay.ResultsScotopic and photopic ERG responses declined in aged mice. Glucose metabolism, glutamine metabolism, OCR, and ATP pools in retinal explants were mostly unaffected by the age of the mouse. In eyecups, glutamine usage in the Krebs Cycle decreased while glucose metabolism, OCR, and ATP pools remained stable.ConclusionsThe ex vivo approach in our study to examine aging glucose and glutamine metabolism in retina and RPE showed negligible impact of age on retina and an impairment of glutamine anaplerosis in eyecups. The surprising metabolic stability of these tissues ex vivo suggests age-related metabolic alterations in these tissues may not be intrinsic. Future experiments should focus on determining whether external factors including nutrient supply, oxygen availability, or other structural changes influence ocular metabolism in vivo.

scholarly journals Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

2021 ◽  
Vol 9 ◽  
Author(s):  
Christine M. Sorenson ◽  
Yong-Seok Song ◽  
Ismail S. Zaitoun ◽  
Shoujian Wang ◽  
Barbara A. Hanna ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Choroidal Neovascularization ◽  
Cell Function ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Endothelial Cell Migration ◽  
Age Related

Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine’s ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities.

Epidemiology, Prevalence and Incidence of Rhegmatogenous Retinal Detachment

2019 ◽  
pp. 135-137
Keyword(s):  
Risk Factors ◽  
Retinal Detachment ◽  
High Myopia ◽  
Rhegmatogenous Retinal Detachment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Subretinal Fluid ◽  
Cataract Extraction ◽  
Common Type ◽  
Associated Risk Factors

Rhegmatogenous retinal detachment is the most common type of retinal detachments and occurs when subretinal fluid accumulates between the neurosensorial retina and retinal pigment epithelium. Although often caused by vitreous liquefaction, cataract extraction, high myopia, inflammation, and trauma are other associated risk factors. In this article, epidemiology, prevalence, and incidence of rhegmatogenous retinal detachment are aimed to describe.

scholarly journals Novel Adeno-Associated Virus Serotypes Efficiently Transduce Murine Photoreceptors

2007 ◽  
Vol 81 (20) ◽  
pp. 11372-11380 ◽  
Author(s):  
Mariacarmela Allocca ◽  
Claudio Mussolino ◽  
Maria Garcia-Hoyos ◽  
Daniela Sanges ◽  
Carolina Iodice ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Therapeutic Success ◽  
Adeno Associated Virus ◽  
Quantitative Manner ◽  
Green Fluorescent ◽  
Rod And Cone Photoreceptors

ABSTRACT Severe inherited retinal diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are caused by mutations in genes preferentially expressed in photoreceptors. While adeno-associated virus (AAV)-mediated gene transfer can correct retinal pigment epithelium (RPE) defects in animal models, approaches for the correction of photoreceptor-specific diseases are less efficient. We evaluated the ability of novel AAV serotypes (AAV2/7, AAV2/8, AAV2/9, AAV2rh.43, AAV2rh.64R1, and AAV2hu.29R) in combination with constitutive or photoreceptor-specific promoters to improve photoreceptor transduction, a limiting step in photoreceptor rescue. Based on a qualitative analysis, all AAV serotypes tested efficiently transduce the RPE as well as rod and cone photoreceptors after subretinal administration in mice. Interestingly, AAV2/9 efficiently transduces Müller cells. To compare photoreceptor transduction from different AAVs and promoters in both a qualitative and quantitative manner, we designed a strategy based on the use of a bicistronic construct expressing both enhanced green fluorescent protein and luciferase. We found that AAV2/8 and AAV2/7 mediate six- to eightfold higher levels of in vivo photoreceptor transduction than AAV2/5, considered so far the most efficient AAV serotype for photoreceptor targeting. In addition, following subretinal administration of AAV, the rhodopsin promoter allows significantly higher levels of photoreceptor expression than the other ubiquitous or photoreceptor-specific promoters tested. Finally, we show that AAV2/7, AAV2/8, and AAV2/9 outperform AAV2/5 following ex vivo transduction of retinal progenitor cells differentiated into photoreceptors. We conclude that AAV2/7 or AAV2/8 and the rhodopsin promoter provide the highest levels of photoreceptor transduction both in and ex vivo and that this may overcome the limitation to therapeutic success observed so far in models of inherited severe photoreceptor diseases.

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