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 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 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 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.

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.

scholarly journals Acute RhoA/Rho Kinase Inhibition is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1927
Author(s):  
Yingyu Mao ◽  
Silvia C. Finnemann
Keyword(s):  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Wild Type ◽  
Phagocytic Capacity ◽  
Photoreceptor Outer Segment ◽  
Rpe Cells ◽  
Rhoa Activity ◽  
Phagocytic Cups

The diurnal phagocytosis of spent photoreceptor outer segment fragments (POS) by retinal pigment epithelial (RPE) cells is essential for visual function. POS internalization by RPE cells requires the assembly of F-actin phagocytic cups beneath surface-tethered POS and Mer tyrosine kinase (MerTK) signaling. The activation of the Rho family GTPase Rac1 is necessary for phagocytic cup formation, and Rac1 is activated normally in MerTK-deficient RPE. We show here that mutant RPE lacking MerTK and wild-type RPE deprived of MerTK ligand both fail to form phagocytic cups regardless of Rac1 activation. However, in wild-type RPE in vivo, a decrease in RhoA activity coincides with the daily phagocytosis burst, while RhoA activity in MerTK-deficient RPE is constant. Elevating RhoA activity blocks phagocytic cup formation and phagocytosis by wild-type RPE. Conversely, inhibiting RhoA effector Rho kinases (ROCKs) rescues both F-actin assembly and POS internalization of primary RPE if MerTK or its ligand are lacking. Most strikingly, acute ROCK inhibition is sufficient to induce the formation and acidification of endogenous POS phagosomes by MerTK-deficient RPE ex vivo. Altogether, RhoA pathway inactivation is a necessary and sufficient downstream effect of MerTK phagocytic signaling such that the acute manipulation of cytosolic ROCK activity suffices to restore phagocytic capacity to MerTK-deficient RPE.

Tissue Translocation Device for Surgical Correction of Age-Related Macular Degeneration

2013 ◽  
Vol 7 (4) ◽  
Author(s):  
George Mathai ◽  
David Rosen ◽  
Shreyes Melkote ◽  
Timothy Olsen
Keyword(s):  
Shape Memory ◽  
Macular Degeneration ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Potential Method ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Age Related

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world in those over age 60. While this disorder is complex, the origin of injury appears to be at the level of the retinal pigment epithelium (RPE), Bruchs membrane, and inner choroid. A potential method to replace damaged tissue in AMD is to harvest healthy donor tissue (RPE-Bruchs-Choroid) from an eye and translocate it to the injured subretinal region. Such an autograft avoids immune mediated rejection and can theoretically restore function to the neurosensory retina (light sensitive part of the retina) by restoring the damaged tissue. Such a procedure requires the design of a device that mechanically supports the integrity of the graft while inside the eye, without injuring or disrupting the tissue. This paper presents the systematic design and manufacture of a thin shape memory foil-based tissue translocation device. The selected embodiment of the design uses thermal adhesion of the tissue to the foil surfaces for tissue support. The shape memory effect enables insertion of the device into the eye via a small incision. The device is manufactured using micromachining techniques and has been tested both ex vivo and in vivo with acceptable anatomic results.

scholarly journals Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function

2018 ◽  
Vol 150 (4) ◽  
pp. 571-590 ◽  
Author(s):  
Philip D. Kiser ◽  
Jianye Zhang ◽  
Aditya Sharma ◽  
Juan M. Angueyra ◽  
Alexander V. Kolesnikov ◽  
...  
Keyword(s):  
Animal Models ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Light Sensitivity ◽  
Ground Squirrels ◽  
Slow Phase ◽  
Acute Administration ◽  
Visual Cycle ◽  
Cone Photoreceptors

Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Gnat1−/− mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity. Complementary experiments in these animal models using the DES1 inhibitor fenretinide show more modest effects on cone recovery. Collectively, these studies demonstrate a role for continuous RPE65 activity in mammalian cone pigment regeneration and provide further evidence for RPE65-independent regeneration mechanisms.

scholarly journals The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected

2020 ◽  
Vol 295 (8) ◽  
pp. 2324-2335 ◽  
Author(s):  
Rong Xu ◽  
Brianna K. Ritz ◽  
Yekai Wang ◽  
Jiancheng Huang ◽  
Chen Zhao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Retinal Pigment Epithelium ◽  
Nitrogen Metabolism ◽  
De Novo ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Mitochondrial Pyruvate Carrier

Defects in energy metabolism in either the retina or the immediately adjacent retinal pigment epithelium (RPE) underlie retinal degeneration, but the metabolic dependence between retina and RPE remains unclear. Nitrogen-containing metabolites such as amino acids are essential for energy metabolism. Here, we found that 15N-labeled ammonium is predominantly assimilated into glutamine in both the retina and RPE/choroid ex vivo. [15N]Ammonium tracing in vivo show that, like the brain, the retina can synthesize asparagine from ammonium, but RPE/choroid and the liver cannot. However, unless present at toxic concentrations, ammonium cannot be recycled into glutamate in the retina and RPE/choroid. Tracing with 15N-labeled amino acids show that the retina predominantly uses aspartate transaminase for de novo synthesis of glutamate, glutamine, and aspartate, whereas RPE uses multiple transaminases to utilize and synthesize amino acids. Retina consumes more leucine than RPE, but little leucine is catabolized. The synthesis of serine and glycine is active in RPE but limited in the retina. RPE, but not the retina, uses alanine as mitochondrial substrates through mitochondrial pyruvate carrier. However, when the mitochondrial pyruvate carrier is inhibited, alanine may directly enter the retinal mitochondria but not those of RPE. In conclusion, our results demonstrate that the retina and RPE differ in nitrogen metabolism and highlight that the RPE supports retinal metabolism through active amino acid metabolism.

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