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Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic...
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Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 29447

Special Issue Editors

Prof. Dr. Ruth B. Caldwell

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Guest Editor
Cellular Biology & Anatomy, Vascular Biology Center, Augusta University, Augusta, GA, USA
Interests: vascular biology; angiogenesis; neurodegeneration; inflammation; ischemia; diabetes
Special Issues, Collections and Topics in MDPI journals
Dr. Abdelrahman Fouda

E-Mail Website
Co-Guest Editor
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Interests: ischemic retinopathy and stroke
Dr. Syed A. H. Zaidi

E-Mail Website
Guest Editor Assistant
Vascular Biology Center, Augusta University, Augusta, GA 30912, USA
Interests: retinal neurodegeneration; glaucoma; ocular pharmacology; astrogliosis
Dr. Ammar Abdelrahman

E-Mail Website
Guest Editor Assistant
Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA
Interests: diabetes; diabetic retinopathy; blood-retinal barrier; neuro-inflammation

Special Issue Information

Dear Colleagues,

Neurons, in general and specifically in the central nervous system, are highly demanding cells requiring continuous metabolic support, meticulous environmental maintenance and the intricate regulation of immune factors. Therefore, in order to maintain retinal homeostasis, the retinal blood supply is under tight regulation and surveillance by vascular, glial, neuronal, and resident immune cells. Ischemia, glial activation, inflammation, and neurodegeneration are common denominators in the development and progression of the pathogenesis observed in retinal diseases. Despite the recent advances in the treatment of retinal diseases, especially with the advent of anti-VEGF therapy and laser photocoagulation, retinal disease continues to be a major cause of blindness worldwide. Moreover, current treatments require sophisticated expertise and come with the risk of adverse outcomes that discourage ophthalmologists from tackling the diseases at earlier stages. Hence, the search for novel therapeutic modalities with better applicability, accessibility, and safety is continuing.

Advances in experimental models (in vivo, ex vivo, and in vitro) improve the understanding of the pathogenic factors behind retinal diseases and provide better insights into potential therapeutics. Despite the lack of perfect experimental models, studies using pre-clinical models help guide rational experimental design to target unanswered questions and promote the wider applicability of research findings in various pathologies sharing common cell type involvement. 

This Special Issue welcomes contributions (both reviews and research articles) that advance our understanding of the specific responses of the various retinal cells to retinal injury and/or strategies to limit such damage and promote repair. Topics include, but are not limited to, human and experimental studies addressing the following retinopathies:

  1. Diabetic retinopathy;
  2. Ischemic retinopathy (retinal artery or vein occlusion);
  3. Retinopathy of prematurity;
  4. Glaucoma;
  5. Optic neuritis and traumatic optic neuropathy.

Prof. Dr. Ruth B. Caldwell
Dr. Abdelrahman Y. Fouda
Guest Editors

Dr. Syed A. H. Zaidi
Dr. Ammar A. Abdelrahman
Guest Editor Assistants

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • retinopathy
  • neurodegeneration
  • neuro-inflammation
  • neurovascular unit
  • neuroprotection

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Published Papers (9 papers)

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Research

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18 pages, 7799 KiB  
Article
Sustained Retinal Defocus Increases the Effect of Induced Myopia on the Retinal Astrocyte Template
by Carol R. Lin, Abduqodir Toychiev, Reynolds K. Ablordeppey, Miduturu Srinivas and Alexandra Benavente-Perez
Cells 2024, 13(7), 595; https://doi.org/10.3390/cells13070595 - 29 Mar 2024
Viewed by 1133
Abstract
The aim of this article is to describe sustained myopic eye growth’s effect on astrocyte cellular distribution and its association with inner retinal layer thicknesses. Astrocyte density and distribution, retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer (IPL) thicknesses [...] Read more.
The aim of this article is to describe sustained myopic eye growth’s effect on astrocyte cellular distribution and its association with inner retinal layer thicknesses. Astrocyte density and distribution, retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer (IPL) thicknesses were assessed using immunochemistry and spectral-domain optical coherence tomography on seventeen common marmoset retinas (Callithrix jacchus): six induced with myopia from 2 to 6 months of age (6-month-old myopes), three induced with myopia from 2 to 12 months of age (12-month-old myopes), five age-matched 6-month-old controls, and three age-matched 12-month-old controls. Untreated marmoset eyes grew normally, and both RNFL and IPL thicknesses did not change with age, with astrocyte numbers correlating to RNFL and IPL thicknesses in both control age groups. Myopic marmosets did not follow this trend and, instead, exhibited decreased astrocyte density, increased GFAP+ spatial coverage, and thinner RNFL and IPL, all of which worsened over time. Myopic changes in astrocyte density, GFAP+ spatial coverage and inner retinal layer thicknesses suggest astrocyte template reorganization during myopia development and progression which increased over time. Whether or not these changes are constructive or destructive to the retina still remains to be assessed. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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15 pages, 3690 KiB  
Article
Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
by Rosario Amato, Maurizio Cammalleri, Alberto Melecchi, Paola Bagnoli and Vittorio Porciatti
Cells 2023, 12(9), 1272; https://doi.org/10.3390/cells12091272 - 27 Apr 2023
Cited by 7 | Viewed by 1988
Abstract
Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often occur independent [...] Read more.
Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often occur independent of IOP, indicating a multifactorial nature of glaucoma, with the likely contribution of glial and vascular function. The aim of the present study was to provide a comprehensive evaluation of the time course of neuro–glial–vascular changes associated with glaucoma progression. We used DBA/2J mice in the age range of 2–15 months as a spontaneous model of glaucoma with progressive IOP elevation and RGC loss typical of human open-angle glaucoma. We found that the onset of RGC degeneration at 10 months of age coincided with that of IOP elevation and vascular changes such as decreased density, increased lacunarity and decreased tight-junction protein zonula occludens (ZO)-1, while hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were already significantly upregulated at 6 months of age together with the onset of Müller cell gliosis. Astrocytes, however, underwent significant gliosis at 10 months. These results indicate that Müller cell activation occurs well before IOP elevation, with probable inflammatory consequences, and represents an early event in the glaucomatous process. Early upregulation of HIF-1α and VEGF is likely to contribute to blood retinal barrier failure, facilitating RGC loss. The different time courses of neuro–glial–vascular changes during glaucoma progression provide further insight into the nature of the disease and suggest potential targets for the development of efficient therapeutic intervention aside from IOP lowering. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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19 pages, 6558 KiB  
Article
Relative Importance of Different Elements of Mitochondrial Oxidative Phosphorylation in Maintaining the Barrier Integrity of Retinal Endothelial Cells: Implications for Vascular-Associated Retinal Diseases
by Shaimaa Eltanani, Thangal Yumnamcha, Andrew Gregory, Mahmoud Elshal, Mohamed Shawky and Ahmed S. Ibrahim
Cells 2022, 11(24), 4128; https://doi.org/10.3390/cells11244128 - 19 Dec 2022
Cited by 6 | Viewed by 2151
Abstract
Purpose: Mitochondrial dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to investigate the role of different mitochondrial constituents, specifically those of oxidative [...] Read more.
Purpose: Mitochondrial dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to investigate the role of different mitochondrial constituents, specifically those of oxidative phosphorylation (OxPhos), in maintaining the barrier function of RECs. Methods: Electric cell-substrate impedance sensing (ECIS) technology was used to assess in real time the role of different mitochondrial components in the total impedance (Z) of human RECs (HRECs) and its components: capacitance (C) and the total resistance (R). HRECs were treated with specific mitochondrial inhibitors that target different steps in OxPhos: rotenone for complex I, oligomycin for complex V (ATP synthase), and FCCP for uncoupling OxPhos. Furthermore, data were modeled to investigate the effects of these inhibitors on the three parameters that govern the total resistance of cells: Cell–cell interactions (Rb), cell–matrix interactions (α), and cell membrane permeability (Cm). Results: Rotenone (1 µM) produced the greatest reduction in Z, followed by FCCP (1 µM), whereas no reduction in Z was observed after oligomycin (1 µM) treatment. We then further deconvoluted the effects of these inhibitors on the Rb, α, and Cm parameters. Rotenone (1 µM) completely abolished the resistance contribution of Rb, as the Rb became zero immediately after the treatment. Secondly, FCCP (1 µM) eliminated the resistance contribution of Rb only after 2.5 h and increased Cm without a significant effect on α. Lastly, of all the inhibitors used, oligomycin had the lowest impact on Rb, as evidenced by the fact that this value became similar to that of the control group at the end of the experiment without noticeable effects on Cm or α. Conclusion: Our study demonstrates the differential roles of complex I, complex V, and OxPhos coupling in maintaining the barrier functionality of HRECs. We specifically showed that complex I is the most important component in regulating HREC barrier integrity. These observed differences are significant since they could serve as the basis for future pharmacological and gene expression studies aiming to improve the activity of complex I and thereby provide avenues for therapeutic modalities in endothelial-associated retinal diseases. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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18 pages, 6069 KiB  
Article
Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis
by Fang Liu, Moaddey Alfarhan, Leanna Baker, Nidhi Shenoy, Yini Liao, Harry O. Henry-Ojo, Payaningal R. Somanath and S. Priya Narayanan
Cells 2022, 11(24), 4100; https://doi.org/10.3390/cells11244100 - 16 Dec 2022
Cited by 5 | Viewed by 2965
Abstract
Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase [...] Read more.
Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX), is protective against neurodegeneration and inflammation in the models of diabetic retinopathy and excitotoxicity. In the present study, utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined the impact of SMOX blockade on retinal neurodegeneration and optic nerve inflammation. The increased expression of SMOX observed in EAE retinas was associated with a significant loss of retinal ganglion cells, degeneration of synaptic contacts, and reduced visual acuity. MDL 72527-treated mice exhibited markedly reduced motor deficits, improved neuronal survival, the preservation of synapses, and improved visual acuity compared to the vehicle-treated group. The EAE-induced increase in macrophage/microglia was markedly reduced by SMOX inhibition. Upregulated acrolein conjugates in the EAE retina were decreased through MDL 72527 treatment. Mechanistically, the EAE-induced ERK-STAT3 signaling was blunted by SMOX inhibition. In conclusion, our studies demonstrate the potential benefits of targeting SMOX to treat MS-mediated neuroinflammation and vision loss. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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16 pages, 3493 KiB  
Article
The Protective Role of Microglial PPARα in Diabetic Retinal Neurodegeneration and Neurovascular Dysfunction
by Tian Yuan, Lijie Dong, Elizabeth A. Pearsall, Kelu Zhou, Rui Cheng and Jian-Xing Ma
Cells 2022, 11(23), 3869; https://doi.org/10.3390/cells11233869 - 1 Dec 2022
Cited by 7 | Viewed by 2720
Abstract
Microglial activation and subsequent pathological neuroinflammation contribute to diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological microgliosis, remain incompletely understood. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism. The present study [...] Read more.
Microglial activation and subsequent pathological neuroinflammation contribute to diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological microgliosis, remain incompletely understood. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism. The present study aimed to determine if PPARα affects pathological microgliosis in DR. In global Pparα mice, retinal microglia exhibited decreased structural complexity and enlarged cell bodies, suggesting microglial activation. Microglia-specific conditional Pparα−/− (PCKO) mice showed decreased retinal thickness as revealed by optical coherence tomography. Under streptozotocin (STZ)-induced diabetes, diabetic PCKO mice exhibited decreased electroretinography response, while diabetes-induced retinal dysfunction was alleviated in diabetic microglia-specific Pparα-transgenic (PCTG) mice. Additionally, diabetes-induced retinal pericyte loss was exacerbated in diabetic PCKO mice and alleviated in diabetic PCTG mice. In cultured microglial cells with the diabetic stressor 4-HNE, metabolic flux analysis demonstrated that Pparα ablation caused a metabolic shift from oxidative phosphorylation to glycolysis. Pparα deficiency also increased microglial STING and TNF-α expression. Taken together, these findings revealed a critical role for PPARα in pathological microgliosis, neurodegeneration, and vascular damage in DR, providing insight into the underlying molecular mechanisms of microgliosis in this context and suggesting microglial PPARα as a potential therapeutic target. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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18 pages, 7547 KiB  
Article
Destabilizing COXIV in Müller Glia Increases Retinal Glycolysis and Alters Scotopic Electroretinogram
by Nana Yaa Nsiah and Denise M. Inman
Cells 2022, 11(23), 3756; https://doi.org/10.3390/cells11233756 - 24 Nov 2022
Cited by 2 | Viewed by 1938
Abstract
Müller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. [...] Read more.
Müller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. To explore the role of oxidative phosphorylation (OXPHOS) in MG energy production in vivo, we generated and characterized adult mice in which MG have impaired cytochrome c oxidase (COXIV) activity through knockout of the COXIV constituent COX10. Histochemistry and protein analysis showed that COXIV protein levels were significantly lower in knockout mouse retina compared to control. Loss of COXIV activity in MG did not induce structural abnormalities, though oxidative stress was increased. Electroretinography assessment showed that knocking out COX10 significantly impaired scotopic a- and b-wave responses. Inhibiting mitochondrial respiration in MG also altered the retinal glycolytic profile. However, blocking OXPHOS in MG did not significantly exacerbate retinal ganglion cell (RGC) loss or photopic negative response after ocular hypertension (OHT). These results suggest that MG were able to compensate for reduced COXIV stability by maintaining fundamental processes, but changes in retinal physiology and metabolism-associated proteins indicate subtle changes in MG function. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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15 pages, 4386 KiB  
Article
Neuroprotection of Rodent and Human Retinal Ganglion Cells In Vitro/Ex Vivo by the Hybrid Small Molecule SA-2
by Jennifer H. Pham, Gretchen A. Johnson, Rajiv S. Rangan, Charles E. Amankwa, Suchismita Acharya and Dorota L. Stankowska
Cells 2022, 11(23), 3741; https://doi.org/10.3390/cells11233741 - 23 Nov 2022
Cited by 6 | Viewed by 2392
Abstract
The mechanisms underlying the neuroprotective effects of the hybrid antioxidant-nitric oxide donating compound SA-2 in retinal ganglion cell (RGC) degeneration models were evaluated. The in vitro trophic factor (TF) deprivation model in primary rat RGCs and ex vivo human retinal explants were used [...] Read more.
The mechanisms underlying the neuroprotective effects of the hybrid antioxidant-nitric oxide donating compound SA-2 in retinal ganglion cell (RGC) degeneration models were evaluated. The in vitro trophic factor (TF) deprivation model in primary rat RGCs and ex vivo human retinal explants were used to mimic glaucomatous neurodegeneration. Cell survival was assessed after treatment with vehicle or SA-2. In separate experiments, tert-Butyl hydroperoxide (TBHP) and endothelin-3 (ET-3) were used in ex vivo rat retinal explants and primary rat RGCs, respectively, to induce oxidative damage. Mitochondrial and intracellular reactive oxygen species (ROS) were assessed following treatments. In the TF deprivation model, SA-2 treatment produced a significant decrease in apoptotic and dead cell counts in primary RGCs and a significant increase in RGC survival in ex vivo human retinal explants. In the oxidative stress-induced models, a significant decrease in the production of ROS was observed in the SA-2-treated group compared to the vehicle-treated group. Compound SA-2 was neuroprotective against various glaucomatous insults in the rat and human RGCs by reducing apoptosis and decreasing ROS levels. Amelioration of mitochondrial and cellular oxidative stress by SA-2 may be a potential therapeutic strategy for preventing neurodegeneration in glaucomatous RGCs. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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16 pages, 3070 KiB  
Article
Systemic Administration of Pegylated Arginase-1 Attenuates the Progression of Diabetic Retinopathy
by Ammar A. Abdelrahman, Katharine L. Bunch, Porsche V. Sandow, Paul N-M Cheng, Ruth B. Caldwell and R. William Caldwell
Cells 2022, 11(18), 2890; https://doi.org/10.3390/cells11182890 - 16 Sep 2022
Cited by 3 | Viewed by 3080
Abstract
Diabetic retinopathy (DR) is a serious complication of diabetes that results from sustained hyperglycemia, hyperlipidemia, and oxidative stress. Under these conditions, inducible nitric oxide synthase (iNOS) expression is upregulated in the macrophages (MΦ) and microglia, resulting in increased production of reactive oxygen species [...] Read more.
Diabetic retinopathy (DR) is a serious complication of diabetes that results from sustained hyperglycemia, hyperlipidemia, and oxidative stress. Under these conditions, inducible nitric oxide synthase (iNOS) expression is upregulated in the macrophages (MΦ) and microglia, resulting in increased production of reactive oxygen species (ROS) and inflammatory cytokines, which contribute to disease progression. Arginase 1 (Arg1) is a ureohydrolase that competes with iNOS for their common substrate, L-arginine. We hypothesized that the administration of a stable form of Arg1 would deplete L-arginine’s availability for iNOS, thus decreasing inflammation and oxidative stress in the retina. Using an obese Type 2 diabetic (T2DM) db/db mouse, this study characterized DR in this model and determined if systemic treatment with pegylated Arg1 (PEG-Arg1) altered the progression of DR. PEG-Arg1 treatment of db/db mice thrice weekly for two weeks improved visual function compared with untreated db/db controls. Retinal expression of inflammatory factors (iNOS, IL-1β, TNF-α, IL-6) was significantly increased in the untreated db/db mice compared with the lean littermate controls. The increased retinal inflammatory and oxidative stress markers in db/db mice were suppressed with PEG-Arg1 treatment. Additionally, PEG-Arg1 treatment restored the blood–retinal barrier (BRB) function, as evidenced by the decreased tissue albumin extravasation and an improved endothelial ZO-1 tight junction integrity compared with untreated db/db mice. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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Review

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28 pages, 3323 KiB  
Review
Current and Novel Therapeutic Approaches for Treatment of Diabetic Macular Edema
by Muhammad Z. Chauhan, Peyton A. Rather, Sajida M. Samarah, Abdelrahman M. Elhusseiny and Ahmed B. Sallam
Cells 2022, 11(12), 1950; https://doi.org/10.3390/cells11121950 - 17 Jun 2022
Cited by 37 | Viewed by 10024
Abstract
Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME’s pathogenesis is multifactorial. Focal edema tends to occur when primary metabolic abnormalities lead to a persistent hyperglycemic state, causing the development of microaneurysms, often [...] Read more.
Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME’s pathogenesis is multifactorial. Focal edema tends to occur when primary metabolic abnormalities lead to a persistent hyperglycemic state, causing the development of microaneurysms, often with extravascular lipoprotein in a circinate pattern around the focal leakage. On the other hand, diffusion edema is due to a generalized breakdown of the inner blood–retinal barrier, leading to profuse early leakage from the entire capillary bed of the posterior pole with the subsequent extravasation of fluid into the extracellular space. The pathogenesis of DME occurs through the interaction of multiple molecular mediators, including the overexpression of several growth factors, including vascular endothelial growth factor (VEGF), insulin-like growth factor-1, angiopoietin-1, and -2, stromal-derived factor-1, fibroblast growth factor-2, and tumor necrosis factor. Synergistically, these growth factors mediate angiogenesis, protease production, endothelial cell proliferation, and migration. Treatment for DME generally involves primary management of DM, laser photocoagulation, and pharmacotherapeutics targeting mediators, namely, the anti-VEGF pathway. The emergence of anti-VEGF therapies has resulted in significant clinical improvements compared to laser therapy alone. However, multiple factors influencing the visual outcome after anti-VEGF treatment and the presence of anti-VEGF non-responders have necessitated the development of new pharmacotherapies. In this review, we explore the pathophysiology of DME and current management strategies. In addition, we provide a comprehensive analysis of emerging therapeutic approaches to the treatment of DME. Full article
(This article belongs to the Special Issue Understanding Retinopathy at the Neuro-Glial-Vascular Intersection: Mechanisms, and Potential Therapeutic Targets)
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