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We present a case of diagnostic interest; we present the differential diagnosis and the complementary tests necessary to reach it, in addition to highlighting the importance of a correct collection of background and clinical history. A 54-year-old woman with a history of carcinoma of the floor of the mouth treated with radiotherapy and chemotherapy develops ischemic retinopathy. It was necessary to perform a systemic study and differential diagnosis with entities such as ocular ischemic syndrome and radiation retinopathy, due to the similarity in the clinical findings found. Radiation retinopathy should be ruled out in any patient with visual impairment and a history of radiotherapy treatment. A broad differential diagnosis and systemic study are required to rule out entities such as ocular ischemic syndrome and diabetic retinopathy, in addition to early treatment to avoid possible complications., (Copyright © 2024 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: To investigate the possible beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in ischemic retinal angiogenesis and whether AMP-activated protein kinase (AMPK) is involved., Methods: Human retinal microvascular endothelial cells (hRMECs) were exposed to dimethyloxalylglycine (DMOG), a hypoxia-inducible factor hydroxylase inhibitor, in the presence or absence of docosahexaenoic acid (DHA) and small interfering RNA (siRNA) for AMPKα for 24 h. Ischemic factors, endothelial mesenchymal transition marker, endothelial barrier integrity, cell migration, and tube formation were evaluated. Neonatal AMPKα 2 -/- and control wild-type (WT) mice were submitted to an oxygen-induced retinopathy (OIR) protocol; their nursing mother mice were either fed ω3-PUFAs or not. In the end, ischemic markers and endothelial cell proliferation were evaluated in neonatal mouse retinal tissue through immunohistochemical or immunofluorescent assays among all studied groups., Results: Cells exposed to DMOG displayed increased expressions of hypoxic and endothelial mesenchymal transition (vimentin) markers and barrier disarrangement of Zonula Occludens-1 compared to the control, accompanied by increased cellular migration and tube formation (p < 0.05). AMPK activity was significantly decreased. Supplementation with DHA restored the mentioned alterations compared to DMOG (p<0.05). In siRNA AMPKα -treated cells, the beneficial effects observed with DHA were abolished. DHA upregulated G-protein receptor-120 (GPR120), which promptly increased intracellular levels of calcium (p ≤ 0.001), which consequently increased Calcium/calmodulin-dependent protein kinase kinase β expression (CaMKKβ) thus phosphorylating AMPK Thr172 . AMPKα 2 -/- and wild-type (WT) OIR mice exhibited similar retinal ischemic changes, and the oral supplementation with ω3-PUFA efficiently prevented the noticed ischemic alterations only in WT mice, suggesting that AMPKα 2 is pivotal in the protective effects of ω3-PUFA., Conclusions: ω3-PUFAs protect the retina from the effects of ischemic conditions, and this effect occurs via the GPR120-CaMKKβ-AMPK axis. A better understanding of this mechanism might improve the control of pathological angiogenesis in retinal ischemic diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests in this study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neurovespina is a synthetic peptide modified from Occidentalin-1202, a nine amino acid residue peptide isolated from the venom of the social wasp Polybia occidentalis. Previous studies showed that this peptide has a neuroprotective effect on the central nervous system, but its action on the eye has not been explored. So, the objective of this work was to investigate the neuroprotective effect of Neurovespina on the retina and its angiogenic potential in the chicken chorioallantoic membrane (CAM). Retinal ischemia was induced in rats by acute elevation of intraocular pressure (IOP). Electroretinography (ERG) measurements, histopathological and immunohistochemical analysis, and transmission electronic microscopy (TEM) records were performed to check the neuroprotection effect of Neurovespina in the retina of the animals. The angiogenic activity of the peptide was investigated by CAM assay. The results showed that Neurovespina was able to reduce the effects induced by ischemic injury, preventing the reduction of a- and b-waves in the scotopic ERG. Histopathological and immunohistochemistry assays showed that Neurovespina, mainly at 60 μg/ml, protected all layers of the retina. The CAM assay revealed that the peptide promoted the reduction of CAM vessels. So, Neurovespina was able to protect retinal cells from ischemic insult and has an antiangiogenic effect, which can be considered as a promising neuroprotective agent for intravitreal application., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Retinal ischemia, one of the most common cause of visual loss, is associated with blood flow inadequacy and subsequent tissue injury. In this setting, some treatments that can counteract glutamate increase, arouse interest in ischemic pathogenesis. Ketamine, a potent N-methyl-d-aspartate (NMDA) receptor antagonist, provides a neuroprotective pathway via decreasing the excitotoxicity triggered by excess glutamatergic. Thus, the goal of this study was to evaluate the safety of intravitreal use of ketamine and their potential protective effects on retinal cells in retinal ischemia/reperfusion model. Initially, ketamine toxicity was evaluated by cytotoxicity assay and Hen's egg chorioallantoic membrane (HET-CAM) method. Afterward, some ketamine concentrations were tested in rat's eyes to verify the safety of the intravitreal use. To investigate the neuroprotective effect on retinal, a single intravitreal injection of ketamine in concentrations of 0.059 mmol.L -1 and 0.118 mmol.L -1 was performed one day before the retinal injury by ischemia/reperfusion model. After 7 and 15 days, the retina activity was evaluated by electroretinogram (ERG) records and, lastly, by morphological analyzes. Cytotoxicity assay reveals that the maximum ketamine concentration that could reach retinal pigmented epithelium cells is 0.353 mmol.L -1 . HET-CAM assay showed that concentrations above 0.237 mmol.L -1 are irritants to the eye. Thus, Ketamine in concentrations of 0.0237 mmol.L -1 , 0.118 mmol.L-1, and 0.059 mmol.L-1 were selected for in vivo toxicity test. ERG records reveal a tendency of b-wave amplitude to decrease as the luminous intensity increased, in the group receiving ketamine at 0.237 mmol.L -1 . Therefore, ketamine in concentrations at 0.059 mmol.L -1 and 0.118 mmol.L-1 were chosen for the following tests. In the ischemia retinal degeneration model, pretreatment with ketamine was capable to promote a recovery of retinal electrophysiological function minimizing the ischemic effects. In histological analysis, the groups that received intravitreal ketamine showed a number of retinal cells significantly higher than the vehicle group. In TUNEL assay a reduction on TUNEL-positive cells was observed in all the layers for both concentrations which allow to affirm that ketamine contributes to reducing cell death in the retina. Transmission electron microscopy (TEM) reaffirms this finding. Ketamine intravitreal pretreatment showed reduced ultrastructural changes. Our findings demonstrate that ketamine is safe for intravitreal use in doses up to 0.118 mmol.L -1 . They seem to be particularly efficient to protect the retina from ischemic injury., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Studies in experimental ischemia models by permanent bilateral common carotid artery occlusion (BCCAO) have reported reduced retinal electrophysiological function, coupled with inner retinal degeneration and gliosis. In the current study, we tested the hypothesis that long-term (up to 14 days) BCCAO impairs oxygen delivery (DO 2 ), which affects oxygen metabolism (MO 2 ) and extraction fraction (OEF), electrophysiological function, morphology, and biochemical pathways. Twenty-one rats underwent BCCAO (N = 12) or sham surgery (N = 9) and were evaluated in separate groups after 3, 7, or 14 days. Electroretinography (ERG), optical coherence tomography, blood flow and vascular oxygen tension imaging, and morphological and biochemical evaluations were performed in both eyes. Reduced ERG b-wave amplitudes and delayed implicit times were reported at 3, 7, and 14 days following BCCAO. Total retinal blood flow, MO 2 , and DO 2 were reduced in all BCCAO groups. OEF was increased in both 3- and 7-day groups, while no significant difference was observed in OEF at 14 days compared to the sham group. At 14 days following BCCAO, total and inner retinal layer thickness was reduced, while the outer nuclear layer thickness and gliosis were increased. There was an increase in nuclei containing fragmented DNA at 3 days following BCCAO. The compensatory elevation in OEF following BCCAO did not meet the tissue demand, resulting in the subsequent reduction of MO 2 . The associations between retinal MO 2 , DO 2 , and retinal function were shown to be significant in the sequelae of persistent ischemia. In sum, measurements of DO 2 , MO 2 , and OEF may become useful for characterizing salvageable tissue in vision-threatening pathologies.

NADPH oxidases (NOX) are activated in ischemic conditions leading to increases in reactive oxygen species (ROS) and neurotoxicity. The aim of the present study was to investigate the role of NOX in the development of retinal pathologies, associated with excitotoxicity and the evaluation of NOX inhibitors as putative therapeutic agents. Sprague-Dawley rats were used for the induction of the in vivo retinal model of (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA) excitotoxicity. Rats were intravitreally administered with PBS, AMPA (42 nmoles) or AMPA + NOX inhibitors, VAS2870 (pan-NOX inhibitor, 10 -6 -10 -4  M), ML171 (NOX1 inhibitor, 10 -5 , 10 -4  M), and GLX7013114 (NOX4 inhibitor, 10 -4  M). Immunohistochemical studies were performed using antibodies raised against nitrotyrosine, a ROS/oxidative stress marker, bNOS, a neuronal marker for nitric oxide synthase and the macro and microglia markers, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1, respectively. VAS2870 and ML171 showed neuroprotective and anti-inflammatory actions reversing the AMPA induced reduction of bNOS expressing amacrine cells and attenuating macro/microglial activation. GLX7013114 (10 -4  M) did not protect bNOS expressing amacrine cells, but it did attenuate the AMPA induced increase in nitrotyrosine positive cells and activation of glial cells. These results suggest that NOX1, NOX4 and possibly NOX2 (due to the actions of VAS2870) play an important role in the pathophysiology of the retina and that NOX inhibitors are putative neuroprotective and anti-inflammatory agents against retinal abnormalities caused by excitotoxicity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Retinal ischemia leads to an early severe damage of the retina and thus plays an important role in eye diseases such as angle-closure glaucoma or retinal vascular occlusion. In retinal diseases, there is common sense about the affection of the optic nerve by ischemic injury. However, the exact dynamic processes of this optic nerve degeneration are mainly unclear. In this study, retinal ischemia was induced in one eye of Brown-Norway rats by raising the intraocular pressure 60 min to 140 mmHg followed by natural reperfusion. Optic nerves were analyzed at six different points in time: 2, 6, 12, and 24 h as well as 3 and 7 days after ischemic injury. Cell infiltration and moreover signs of tissue demyelination and dissolution were noticed in optic nerves 7 days after ischemia (hematoxylin & eosin: p < 0.001, luxol fast blue: p = 0.04). Although microglial activation was verified already from 12 h on after ischemia (p = 0.030), the beginning of a structural degeneration of the neurofilament was seen at 3 days (p = 0.02). Interestingly, proliferative microglia were present later on (7 days: p = 0.017). At this point, the number of total microglia was also increased in ischemic nerves (p = 0.003). Concluding, our data indicate that not only retinal tissue is affected by an ischemia, the optic nerve also demonstrates progressive damage. Interestingly, a microglia activation was noted days before structural damage became visible., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Retinal vascular diseases, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ocular ischemic syndrome and ischemic optic neuropathy, are leading causes of vision impairment and blindness. Whilst drug, laser or surgery-based treatments for the late stage complications of many of these diseases are available, interventions that target the early vasodegenerative stages are lacking. Progressive vasculopathy and ensuing ischemia is an underpinning pathology in many of these diseases, leading to hypoperfusion, hypoxia, and ultimately pathological neovascularization and/or edema in the retina and other ocular tissues, such as the optic nerve and iris. Therefore, repairing the retinal vasculature may prevent progression of ischemic retinopathies into late stage vascular complications. Various cell types have been explored for their vascular repair potential. Endothelial progenitor cells, mesenchymal stem cells and induced pluripotent stem cells are studied for their potential to integrate with the damaged retinal vasculature and limit ischemic injury. Clinical trials for some of these cell types have confirmed safety and feasibility in the treatment of ischemic diseases, including some retinopathies. Another promising avenue is mobilization of endogenous endothelial progenitors, whereby reparative cells are moved from their niche to circulating blood to target and home into ischemic tissues. Several aspects and properties of these cell types have yet to be elucidated. Nevertheless, we foresee that cell therapy, whether through delivery of exogenous or enhancement of endogenous reparative cells, will become a valuable and beneficial treatment for ischemic retinopathies.

Purpose: Retinal ischemia remains a common sight threatening end-point in blinding diseases such as diabetic retinopathy and retinopathy of prematurity. Endothelial colony forming cells (ECFCs) represent a subpopulation of endothelial progenitors with therapeutic utility for promoting reparative angiogenesis in the ischaemic retina. The current study has investigated the potential of enhancing this cell therapy approach by the dampening of the pro-inflammatory milieu typical of ischemic retina. Based on recent findings that ARA290 (cibinetide), a peptide based on the Helix-B domain of erythropoietin (EPO), is anti-inflammatory and tissue-protective, the effect of this peptide on ECFC-mediated vascular regeneration was studied in the ischemic retina., Methods: The effects of ARA290 on pro-survival signaling and function were assessed in ECFC cultures in vitro. Efficacy of ECFC transplantation therapy to promote retinal vascular repair in the presence and absence of ARA290 was studied in the oxygen induced retinopathy (OIR) model of retinal ischemia. The inflammatory cytokine profile and microglial activation were studied as readouts of inflammation., Results: ARA290 activated pro-survival signaling and enhanced cell viability in response to H 2 O 2 -mediated oxidative stress in ECFCs in vitro. Preconditioning of ECFCs with EPO or ARA290 prior to delivery to the ischemic retina did not enhance vasoreparative function. ARA290 delivered systemically to OIR mice reduced pro-inflammatory expression of IL-1β and TNF-α in the mouse retina. Following intravitreal transplantation, ECFCs incorporated into the damaged retinal vasculature and significantly reduced avascular area. The vasoreparative function of ECFCs was enhanced in the presence of ARA290 but not EPO., Discussion: Regulation of the pro-inflammatory milieu of the ischemic retina can be enhanced by ARA290 and may be a useful adjunct to ECFC-based cell therapy for ischemic retinopathies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To localize and quantify ischemic changes induced by proton beam irradiation of central choroidal melanoma and to identify baseline predictors correlated with the extent of ischemic changes., Methods: Retrospective chart review of patients with central choroidal melanoma treated by proton beam irradiation and conducted widefield fluorescein angiography (≥ 20 months after radiation therapy). Quantification and location of ischemic areas and correlation to baseline predictors. Multiple linear regression model was performed for analyses., Results: Twenty-five eyes from 25 patients were included in final analysis. Mean largest basal tumor area was 56.6 ± 40.0 mm 2 and mean maximal tumor prominence 2.5 ± 1.4 mm. Mean total radiated area was 339.1 ± 68.3 mm 2 . All patients showed ischemic changes. Mean ischemic area was 387.6 ± 123.3 mm 2 and mean ischemic index (ischemic area/total visible area) was 0.53 ± 0.23. Twenty-two patients (88%) presented ischemic changes outside of the irradiation field, which comprised of 23% of total ischemic area. Mean angular distance between lateral border of irradiation field and ischemic area outside of the radiated area was 44.8 ± 36.5°. Multivariable analysis revealed a positive correlation of total ischemic area with total radiated area (p = 0.02) and initial sonographic tumor prominence (p = 0.02)., Conclusions: Ischemic changes induced by proton beam irradiation of central choroidal melanoma were localized and quantified. Ischemic changes exceed the tumor area distinctly and are found also outside of the irradiation field in the majority of patients. Size of irradiation area and tumor prominence are positively correlated with extent of ischemic area.

Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate. Vinpocetine's actions to improve cation channel permeability and cell marker immunoreactivity following ischemia appeared to be limited to NMDA activation with no changes observed following kainate stimulation. Vinpocetine's actions were lost in the presence of an NMDA receptor inhibitor further suggesting they may be secondary to NMDA receptor activation. NMDA receptor function was also necessary for vinpocetine's actions on glucose availability during ischemia but not lactate dehydrogenase (LDH) activity in the ischemic retina suggesting not all of vinpocetine's actions are linked to NMDA receptor function. These results may explain vinpocetine's effectiveness as a neuroprotective agent as the NMDA receptor is implicated in the pathogenesis of ischemia in a range of tissues of the central nervous system., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Exosomes derived from human mesenchymal stem cells (hMSCs) cultured under hypoxic conditions contain proteins and growth factors that promote angiogenesis. This study investigated the effect of intravitreal administration of these exosomes on retinal ischemia using a murine model., Methods: Oxygen-induced retinopathy (OIR) was induced by exposing one-week-old male C57BL/6J mice to 5 days of 75% hyperoxic conditioning, and returning to room air. After hyperoxic conditioning, the right eye of each mouse was injected intravitreally with 1 µl saline or exosomes derived from hMSCs and compared to control mice of the same age raised in room air without OIR injected intravitreally with saline. Two weeks post-injection, fluorescein angiography (FA) and phase-variance optical coherence tomography angiography (pvOCTA) were used to assess retinal perfusion. Retinal thickness was determined by OCT. The extent of retinal neovascularization was quantitated histologically by counting vascular nuclei on the retinal surface., Results: Among eyes with OIR, intravitreal exosome treatment partially preserved retinal vascular flow in vivo and reduced associated retinal thinning; retinal thickness on OCT was 111.1 ± 7.4µm with saline versus 132.1 ± 11.6µm with exosome, p < 0.001. Retinal neovascularization among OIR eyes was reduced with exosome treatment when compared to saline-treated eyes (7.75 ± 3.68 versus 2.68 ± 1.35 neovascular nuclei per section, p < 0.0001). No immunogenicity or ocular/systemic adverse effect was associated with intravitreal exosome treatment., Conclusions: Intravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration.

Vinpocetine has been shown to have beneficial effects for tissues of the central nervous system subjected to ischemia and other related metabolic insults. We recently showed vinpocetine promotes glucose availability, prevents unregulated cation channel permeability and regulates glial reactivity when present during retinal ischemia. Less is known however about the ability of vinpocetine to protect against future ischemic insults. This study explores the effect of vinpocetine when used as a pre-treatment in an ex vivo model for retinal ischemia using cation channel permeability of agmatine (AGB) combined with immunohistochemistry as a measure for cell functionality. We found that vinpocetine pre-treatment reduced cation channel permeability and apoptotic marker immunoreactivity in the GCL and increased parvalbumin immunoreactivity of inner retinal neurons in the inner nuclear layer following ischemic insult. Vinpocetine pre-treatment also reduced Müller cell reactivity following ischemic insults of up to 120 min compared to untreated controls. Many of vinpocetine's effects however were transient in nature suggesting the drug can protect retinal neurons against future ischemic damage but may have limited long-term applications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: While methemoglobinemia is a possible complication of chronic dapsone therapy or of acute overdose, serious adverse manifestations related to methemoglobin formation remain rare. We present an unusual case with severe ischemic retinal injury., Case Report: A 30-year-old African woman presented with a sudden decrease of visual acuity secondary to retinal ischemia. She was chronically treated with dapsone (50 mg/day) for a dermatologic disease and denied any drug overdose. However, the determination of serum dapsone level on admission revealed a largely supratherapeutic concentration (20,044 μg/ml compared with 1-3.5 ± 0.5 μg/ml for therapeutic levels). The methemoglobin level at admission was 32% (sulfhemoglobin 1.2%), with hemoglobin level, 7.4 g/dl, schistocytes count, 2-5%, lactate dehydrogenase level, 580 IU/l, and haptoglobin level, < 10 mg/dl. The patient had both alpha-thalassemia and sickle cell trait. She was treated with methylene blue, vitamin C, and exchange transfusion. There was no improvement in visual symptoms over time., Conclusions: In a patient with supratherapeutic serum levels of dapsone, the severity of visual injury was associated with dapsone-induced methemoglobinemia and hemolysis, and perhaps also with some hematologic predisposing factors.

Ocular ischemic syndrome is likely stem from retinal ischemia, and which causes visual disorder. The pathological mechanism of ocular ischemic syndrome is still unknown, therefore the optimal treatment for ocular ischemic syndrome remains to be established. Then, this study aimed to evaluate the effects of tissue-derived kallidinogenase in retinal ischemia protection in mice. In the present study, the effects of tissue-derived kallidinogenase (1 or 10 μg/kg, i.v.) on ischemia/reperfusion-induced retinal damage in mice were examined by histological, electrophysiological, and permeability analyses. In addition, we assessed phosphorylation of endothelial nitric oxide synthase (eNOS) and nuclear factor-kappa B (NF-κB), which is closely-involved in ischemic injury and permeability. Moreover, the neuroprotective effect of kallidinogenase in an in vitro model of ischemia induced by oxygen-glucose deprivation or hypoxia was examined. The results indicated that kallidinogenase significantly prevented the decrease in ganglion cell number induced by ischemia/reperfusion. Electroretinogram measurements showed that kallidinogenase significantly prevented the ischemia/reperfusion-induced reductions in a- and b-wave amplitudes seen 5 days after ischemia/reperfusion. Moreover, kallidinogenase significantly inhibited the permeability increase induced by ischemia/reperfusion. Similar to the results in vivo, kallidinogenase significantly inhibited the retinal ganglion cell death induced by oxygen-glucose deprivation. Also, kallidinogenase significantly suppressed the hypoxia-induced increase in permeability. However, these effects observed in vitro disappeared when an eNOS inhibitor was used concurrently. These findings suggest that kallidinogenase may prevent ischemia/reperfusion-induced retinal damage, might be through eNOS activation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

IntroductionFew studies have explored MultiColor™ imaging (MCI) in evaluating retinal vascular diseases, particularly branch retinal vein occlusion (BRVO). This study aimed to compare the identification of retinal vessel whitening in BRVO using MCI by scanning confocal laser versus conventional white-flash color fundus photography (CFP).MethodsPaired images of consecutive patients diagnosed with BRVO who underwent same-day MCI and CFP were reviewed. Visualization of vessel whitening on MCI and CFP was graded and scored using a scale by two masked graders. A longitudinal analysis of the vessel grading score was performed to evaluate the vessel whitening detection by MCI. A correlation analysis was conducted between vessel whitening on MCI and the measured area of retinal ischemia on fluorescein angiography to evaluate the MCI performance.ResultsForty-four eyes of 41 patients (mean age 69 ± 14 years; 61% female) were analyzed. MCI demonstrated superior vessel whitening visibility score than CFP (p < 0.001). Longitudinal analysis showed no significant changes in vessel whitening visibility scores over a mean follow-up time of 430 ± 648 days (p = 0.655). There was a significantly positive correlation between the grading score of vessels whitening by MCI and the area of ischemia by fluorescein angiography (r2 = 0.15; p = 0.036).ConclusionMCI appears to provide a superior detection of whitening BRVO compared to CFP, serving as a rapid and non-invasive correlate of retinal ischemia.

Retinal ischemia plays a vital role in vision-threatening retinal ischemic disorders, such as diabetic retinopathy, age-related macular degeneration, glaucoma, etc. The aim of this study was to investigate the effects of S-allyl L-cysteine (SAC) and its associated therapeutic mechanism. Oxidative stress was induced by administration of 500 μM H2O2 for 24 h; SAC demonstrated a dose-dependent neuroprotective effect with significant cell viability effects at 100 μM, and it concurrently downregulated angiogenesis factor PKM2 and inflammatory biomarker MCP-1. In a Wistar rat model of high intraocular pressure (HIOP)-induced retinal ischemia and reperfusion (I/R), post-administration of 100 μM SAC counteracted the ischemic-associated reduction of ERG b-wave amplitude and fluorogold-labeled RGC reduction. This study supports that SAC could protect against retinal ischemia through its anti-oxidative, anti-angiogenic, anti-inflammatory, and neuroprotective properties. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) overactivity has been implicated as a factor contributing to glaucomatous neuropathy, and it has been utilized in animal models of retinal ischemia. The functional effects of long-term ET-1 exposure and possible compensatory mechanisms have, however, not been investigated. This was therefore the purpose of our study. ET-1 was delivered into rat eyes via a single intravitreal injection of 500 µM or via transgene delivery using an adeno-associated viral (AAV) vector. Retinal function was assessed using electroretinography (ERG) and the retinal expression of potentially compensatory genes was evaluated by means of qRT-PCR. Acute ET-1 delivery led to vasoconstriction and a significant reduction in the ERG response. AAV–ET-1 resulted in substantial transgene expression and ERG results similar to the acute ET-1 injections and comparable to other models of retinal ischemia. Compensatory changes were observed, including an increase in calcitonin gene-related peptide (CGRP) gene expression, which may both counterbalance the vasoconstrictive effects of ET-1 and provide neuroprotection. This chronic ET-1 ischemia model might be especially relevant to glaucoma research, mimicking the mild and repeated ischemic events in patients with long-term vascular dysfunction. The compensatory mechanisms, and particularly the role of vasodilatory CGRP in mitigating the retinal damage, warrant further investigation with the aim of evaluating new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis. Early diagnosis and initiation of thromboprophylaxis reduce the risk of recurrent thrombosis. In this report, we presented a case with no known systemic disease but diagnosed as primary APS based on retinal ischemia findings in fluorescein angiography and optic coherence tomography angiography. The aim of this report is to emphasize that APS, which causes thrombosis in vital organs, can occur with retinal ischemia and that the diagnosis of the disease by an ophthalmologist can be life-saving. [ABSTRACT FROM AUTHOR]

Ischemic retinal damage, a common condition associated with retinal vascular occlusion, glaucoma, diabetic retinopathy, and other eye diseases, threatens the vision of millions of people worldwide. It triggers excessive inflammation, oxidative stress, apoptosis, and vascular dysfunction, leading to the loss and death of retinal ganglion cells. Unfortunately, minority drugs are available for treating retinal ischemic injury diseases, and their safety are limited. Therefore, there is an urgent need to develop more effective treatments for ischemic retinal damage. Natural compounds have been reported to have antioxidant, anti-inflammatory, and antiapoptotic properties that can be used to treat ischemic retinal damage. In addition, many natural compounds have been shown to exhibit biological functions and pharmacological properties relevant to the treatment of cellular and tissue damage. This article reviews the neuroprotective mechanisms of natural compounds involve treating ischemic retinal injury. These natural compounds may serve as treatments for ischemia-induced retinal diseases. [ABSTRACT FROM AUTHOR]

Purpose: Retinal ischemia (RI) and progressive neuronal death are sight-threatening conditions. Mitochondrial (mt) dysfunction and fusion/fission processes have been suggested to play a role in the pathophysiology of RI. This study focuses on changes in the mt parameters of the neuroretina, retinal pigment epithelium (RPE) and choroid in a porcine high intraocular pressure (IOP)-induced RI minipig model. Methods: In one eye, an acute IOP elevation was induced in minipigs and compared to the other control eye. Activity and amount of respiratory chain complexes (RCC) were analyzed by spectrophotometry and Western blot, respectively. The coenzyme Q10 (CoQ10) content was measured using HPLC, and the ultrastructure of the mt was studied via transmission electron microscopy. The expression of selected mt-pathway genes was determined by RT-PCR. Results: At a functional level, increased RCC I activity and decreased total CoQ10 content were found in RPE cells. At a protein level, CORE2, a subunit of RCC III, and DRP1, was significantly decreased in the neuroretina. Drp1 and Opa1, protein-encoding genes responsible for mt quality control, were decreased in most of the samples from the RPE and neuroretina. Conclusions: The eyes of the minipig can be considered a potential RI model to study mt dysfunction in this disease. Strategies targeting mt protection may provide a promising way to delay the acute damage and onset of RI. [ABSTRACT FROM AUTHOR]

Purpose: Retinal ischemia/reperfusion (I/R) injury is a common cause of visual impairment and blindness for which there remain limited treatment options. Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT), have been shown to block the NLRP3 inflammasome and prevent retinal degeneration in a mouse model of age-related macular degeneration. The NLRP3 inflammasome has also been shown to be triggered in I/R injury. Therefore, we studied the neuroprotective effects of AZT using a pressure-induced retinal ischemia mouse model. Methods: C57BL/6J mice were randomly assigned to 1 of 2 treatment groups: vehicle-treated retinal I/R injury (n = 6) or AZT-treated retinal I/R injury (n = 6). Vehicle (1% dimethyl sulfoxide [DMSO] in phosphate-buffered saline [PBS]) or AZT 50 mg/kg in 1% DMSO in PBS were injected intraperitoneally twice daily for 5 days. On day 2 of treatment, retinal ischemia was induced by transient elevation of intraocular pressure for 45 min. Scotopic electroretinography (ERG) was used to quantify retinal function before and 1 week after retinal ischemic insult. Retinal morphology was examined 1 week after ischemic insult. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and caspase 1 immunostaining was performed 24 h after retinal I/R injury. Results: Following I/R injury, ERG a- and b-wave amplitudes were significantly reduced in the vehicle-treated mice. AZT treatment significantly attenuated I/R-induced loss of retinal function as compared with vehicle-treated mice. Additionally, AZT-treated mice experienced significantly less inner retinal thinning as compared with vehicle-treated mice. TUNEL-positive cells were prevalent in the vehicle-treated I/R injury mouse retinas compared with the AZT-treated I/R injury mouse retinas. More caspase-1 immunoreactivity was detected in ganglion cell layer and inner nuclear layer (INL) in vehicle-treated I/R injury group than in AZT-treated I/R injury group. Conclusion: AZT treatment resulted in relative preservation of retinal structure and function following ischemic insult as compared with controls. This suggests AZT may have therapeutic value in the management of retinal ischemic diseases. [ABSTRACT FROM AUTHOR]

Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.

Cyclosporin A (CsA) inhibits the opening of the mitochondrial permeability transition pore (MPTP) by interacting with cyclophilin D (CypD) and ameliorates neuronal cell death in the central nervous system against ischemic injury. However, the molecular mechanisms underlying CypD/MPTP opening-mediated cell death in ischemic retinal injury induced by acute intraocular pressure (IOP) elevation remain unknown. We observed the first direct evidence that acute IOP elevation significantly upregulated CypD protein expression in ischemic retina at 12 h. However, CsA prevented the upregulation of CypD protein expression and promoted retinal ganglion cell (RGC) survival against ischemic injury. Moreover, CsA blocked apoptotic cell death by decreasing cleaved caspase-3 protein expression in ischemic retina. Of interest, although the expression level of Bcl-xL protein did not show a significant change in ischemic retina treated with vehicle or CsA at 12 h, ischemic damage induced the reduction of Bcl-xL immunoreactivity in RGCs. More importantly, CsA preserved Bcl-xL immunoreactivity in RGCs of ischemic retina. In parallel, acute IOP elevation significantly increased phosphorylated Bad (pBad) at Ser112 protein expression in ischemic retina at 12 h. However, CsA significantly preserved pBad protein expression in ischemic retina. Finally, acute IOP elevation significantly increased mitochondrial transcription factor A (Tfam) protein expression in ischemic retina at 12 h. However, CsA significantly preserved Tfam protein expression in ischemic retina. Studies on mitochondrial DNA (mtDNA) content in ischemic retina showed that there were no statistically significant differences in mtDNA content among control and ischemic groups treated with vehicle or CsA. Therefore, these results provide evidence that the activation of CypD-mediated MPTP opening is associated with the apoptotic pathway and the mitochondrial alteration in RGC death of ischemic retinal injury. On the basis of these observations, our findings suggest that CsA-mediated CypD inhibition may provide a promising therapeutic potential for protecting RGCs against ischemic injury-mediated mitochondrial dysfunction.

In this case, we demonstrate the ability of diffusion weighted magnetic resonance imaging to localize retinal ischemia in a patient with acute vision loss. MRI is widely used for the evaluation of acute stroke, but there has only been one other case report showing the ability of DWI to rapidly localize retinal pathology, including central retinal artery occlusion [1]. Central retinal artery occlusion is an ocular emergency presenting with acute, painless loss of vision as a result of retinal ischemia. This case demonstrates the role of diffusion weighted imaging as an adjunctive test in the prompt diagnosis and management of central retinal artery occlusion. As the technology improves, we anticipate diffusion weighted imaging will become more sensitive for the identification of acute retinal ischemia and other retinal pathologies. • DWI is currently the most sensitive sequence for the diagnosis of stroke. • Little research exists on the use of DWI in detection of central retinal artery occlusion (CRAO). • Diagnosis of CRAO is time sensitive, but history and fundoscopic exam findings may not always allow early detection. • This case describes DWI in the visualization of retinal ischemia and its use as an adjunctive test in the diagnosis of CRAO. [ABSTRACT FROM AUTHOR]

Retinal ischemia is a common pathomechanism in many ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, glaucoma or retinal vascular occlusion. Several studies demonstrated that ischemia/reperfusion (I/R) leads to morphological and functional changes of different retinal cell types. However, little is known about the ischemic effects on the optic nerve. The goal of this study was to evaluate these effects. Ischemia was induced by raising the intraocular pressure (IOP) in one eye of rats to 140 mmHg for 1 h followed by natural reperfusion. After 21 days, histological as well as quantitative real-time PCR (qRT-PCR) analyses of optic nerves were performed. Ischemic optic nerves showed an infiltration of cells and also degeneration with signs of demyelination. Furthermore, a migration and an activation of microglia could be observed histologically as well as on mRNA level. In regard to macroglia, a trend toward gliosis could be noted after ischemia induction by vimentin staining. Additionally, an up-regulation of glial fibrillary acidic protein (GFAP) mRNA was found in ischemic optic nerves. Counting of oligodendrocyte transcription factor 2 positive (Olig2C) cells revealed a decrease of oligodendrocytes in the ischemic group. Also, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) mRNA expression was down-regulated after induction of I/R. On immunohistological level, a decrease of MOG was detectable in ischemic optic nerves as well. In addition, SMI-32 stained neurofilaments of longitudinal optic nerve sections showed a strong structural damage of the ischemic optic nerves in comparison to controls. Consequently, retinal ischemia impacts optic nerve degeneration. These findings could help to better understand the course of destruction in the optic nerve after an ischemic insult. Especially for therapeutic studies, the optic nerve is important because of its susceptibility to be damaged as a result to retinal ischemic injury and also its connecting function between the eye and the brain. So, future drug screenings should target not only the retina, but also the functionality and structure of the optic nerve. In the future, these results could lead to the development of new therapeutic strategies for treatment of ischemic injury. [ABSTRACT FROM AUTHOR]

Background and Objective: To compare a single image with a computer-generated summarized image from the ultra-wide-field fluorescein angiogram (UWFFA) sequence for evaluation of ischemic index (ISI).Materials and Methods: UWFFA sequences from patients with diabetic retinopathy (DR) (n=5), branch retinal vein occlusion (BRVO) (n=5), and central retinal vein occlusion (CRVO) (n=5) were evaluated by six graders. A single image best illustrating retinal non-perfusion was compared to a summarized image generated by computerized superimposition of angiograms. Non-perfused and ungradable retinal areas were outlined and the ISI between the single and summarized images was compared.Results: The mean ISI in the single versus (vs) summarized images was 17% vs 15% in BRVO (p=0.12), 48% vs 48% in CRVO (p=0.67), and 25% vs 23% in DR (p=0.005). Inter-grader agreement of ISI in single versus summarized images was 0.43 vs 0.40 in BRVO, 0.69 vs 0.71 in CRVO, and 0.53 vs 0.34 in DR.Conclusion: Computer-generated summarized images were similar to single images for grading ISI in BRVO and CRVO, but underestimated it in DR. [ABSTRACT FROM AUTHOR]

Background: Retinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Some studies propose that miRs predominantly target the TFs rather than other types of protein coding genes and such studies suggest a possible interconnection of these two regulators in co-regulatory networks. Results: Our lab has generated mRNA and miRNA microarray expression data to investigate time-dependent changes in gene expression, following induction of ischemia-reperfusion (IR) injury in the rat retina. Data from different reperfusion time points following retinal IR-injury were analyzed. Paired expression data for miRNA-target gene (TG), TF-TG, miRNA-TF were used to identify regulatory loop motifs whose expressions were altered by the IR injury paradigm. These loops were subsequently integrated into larger regulatory networks and biological functions were assayed. Systematic analyses of the networks have provided new insights into retinal gene regulation in the early and late periods of IR. We found both overlapping and unique patterns of molecular expression at the two time points. These patterns can be defined by their characteristic molecular motifs as well as their associated biological processes. We highlighted the regulatory elements of miRs and TFs associated with biological processes in the early and late phases of ischemia-reperfusion injury. Conclusions: The etiology of retinal ischemia-reperfusion injury is orchestrated by complex and still not well understood gene networks. This work represents the first large network analysis to integrate miRNA and mRNA expression profiles in context of retinal ischemia. It is likely that an appreciation of such regulatory networks will have prognostic potential. In addition, the computational framework described in this study can be used to construct miRNA-TF interactive systems networks for various diseases/disorders of the retina and other tissues. [ABSTRACT FROM AUTHOR]

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Iron is an important micronutrient for neuronal function and survival. It plays an essential role in DNA and protein synthesis, neurotransmission and electron transport chain due to its dual redox states. On the contrary, iron also catalyses the production of free radicals and hence, causes oxidative stress. Therefore, maintenance of iron homeostasis is very crucial and it involves a number of proteins in iron metabolism and transport that maintain the balance. In ischemic conditions large amount of iron is released and this free iron catalyzes production of more free radicals and hence, causing more damage. In this review we have focused on the iron transport and maintenance of iron homeostasis at large and also the effect of imbalance in iron homeostasis on retinal and brain tissue under ischemic conditions. The understanding of the proteins involved in the homeostasis imbalance will help in developing therapeutic strategies for cerebral as well retinal ischemia. [ABSTRACT FROM AUTHOR]