Editorial

4 pages, 178 KiB

Open AccessEditorial

Towards an Understanding of Retinal Diseases and Novel Treatment

by Stephanie C. Joachim

Int. J. Mol. Sci. 2022, 23(14), 7576; https://doi.org/10.3390/ijms23147576 - 08 Jul 2022

Viewed by 1110

The Special Issue, “Towards an Understanding of Retinal Diseases and Novel Treatment”, provides comprehensive information on retinal diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, retinitis pigmentosa (RP), and others [...] Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

Research

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16 pages, 3767 KiB

Open AccessArticle

Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve

by Magdalena Schneider, Andrea E. Dillinger, Andreas Ohlmann, Renato V. Iozzo and Rudolf Fuchshofer

Int. J. Mol. Sci. 2021, 22(14), 7660; https://doi.org/10.3390/ijms22147660 - 17 Jul 2021

Cited by 11 | Viewed by 2661

Abstract

During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-β) 2 levels. In this study we tested the hypothesis if the presence [...] Read more.

During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-β) 2 levels. In this study we tested the hypothesis if the presence or absence of decorin (DCN), a small leucine-rich proteoglycan and a natural inhibitor of several members of the TGF family, would affect the expression of the TGF-βs and connective tissue growth factor (CTGF/CCN2) in human ONH astrocytes and murine ON astrocytes. We found that DCN is present in the mouse ON and is expressed by human ONH and murine ON astrocytes. DCN expression and synthesis was significantly reduced after 24 h treatment with 3 nM CTGF/CCN2, while treatment with 4 pM TGF-β2 only reduced expression of DCN significantly. Conversely, DCN treatment significantly reduced the expression of TGF-β1, TGF-β2 and CTGF/CCN2 vis-a-vis untreated controls. Furthermore, DCN treatment significantly reduced expression of fibronectin (FN) and collagen IV (COL IV). Notably, combined treatment with DCN and triciribine, a small molecule inhibitor of protein kinase B (AKT), attenuated effects of DCN on CTGF/CCN2, TGF-β1, and TGF-β2 mRNA expression. We conclude (1) that DCN is an important regulator of TGF-β and CTGF/CCN2 expression in astrocytes of the ON and ONH, (2) that DCN thereby regulates the expression of extracellular matrix (ECM) components and (3) that DCN executes its negative regulatory effects on TGF-β and CTGF/CCN2 via the pAKT/AKT signaling pathway in ON astrocytes. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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19 pages, 2679 KiB

Open AccessArticle

Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation

by Oliver W. Gramlich, Cheyanne R. Godwin, David Wadkins, Benjamin W. Elwood and Markus H. Kuehn

Int. J. Mol. Sci. 2021, 22(14), 7581; https://doi.org/10.3390/ijms22147581 - 15 Jul 2021

Cited by 7 | Viewed by 4373

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. [...] Read more.

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABA_A receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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22 pages, 4510 KiB

Open AccessArticle

The Lrat^−/− Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa

by Céline Koster, Koen T. van den Hurk, Colby F. Lewallen, Mays Talib, Jacoline B. ten Brink, Camiel J. F. Boon and Arthur A. Bergen

Int. J. Mol. Sci. 2021, 22(13), 7234; https://doi.org/10.3390/ijms22137234 - 05 Jul 2021

Cited by 7 | Viewed by 3050

Abstract

Purpose: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), causing a dysfunctional visual (retinoid) [...] Read more.

Purpose: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), causing a dysfunctional visual (retinoid) cycle. Methods: The introduced mutation was confirmed by DNA and RNA sequencing. The expression of Lrat was determined on both the RNA and protein level in wildtype and knockout animals using RT-PCR and immunohistochemistry. The retinal structure and function, as well as the visual behavior of the Lrat^−/− and control rats, were characterized using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) and vision-based behavioral assays. Results: Wildtype animals had high Lrat mRNA expression in multiple tissues, including the eye and liver. In contrast, hardly any expression was detected in Lrat^−/− animals. LRAT protein was abundantly present in wildtype animals and absent in Lrat^−/− animals. Lrat^−/− animals showed progressively reduced ERG potentials compared to wildtype controls from two weeks of age onwards. Vison-based behavioral assays confirmed reduced vision. Structural abnormalities, such as overall retinal thinning, were observed in Lrat^−/− animals. The retinal thickness in knockout rats was decreased to roughly 80% by four months of age. No functional or structural differences were observed between wildtype and heterozygote animals. Conclusions: Our Lrat^−/− rat is a new animal model for retinal dystrophy, especially for the LRAT-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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18 pages, 1968 KiB

Open AccessArticle

Identification of Novel Genomic-Variant Patterns of OR56A5, OR52L1, and CTSD in Retinitis Pigmentosa Patients by Whole-Exome Sequencing

by Ting-Yi Lin, Yun-Chia Chang, Yu-Jer Hsiao, Yueh Chien, Ying-Chun Jheng, Jing-Rong Wu, Lo-Jei Ching, De-Kuang Hwang, Chih-Chien Hsu, Tai-Chi Lin, Yu-Bai Chou, Yi-Ming Huang, Shih-Jen Chen, Yi-Ping Yang and Ping-Hsing Tsai

Int. J. Mol. Sci. 2021, 22(11), 5594; https://doi.org/10.3390/ijms22115594 - 25 May 2021

Cited by 2 | Viewed by 2367

Abstract

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel [...] Read more.

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia. Full article

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16 pages, 6533 KiB

Open AccessArticle

Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

by Viktoria Constanze Brücher, Charlotte Egbring, Tanja Plagemann, Pavel I. Nedvetsky, Verena Höffken, Hermann Pavenstädt, Nicole Eter, Joachim Kremerskothen and Peter Heiduschka

Int. J. Mol. Sci. 2021, 22(10), 5321; https://doi.org/10.3390/ijms22105321 - 18 May 2021

Cited by 3 | Viewed by 2131

Abstract

The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age [...] Read more.

The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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14 pages, 4930 KiB

Open AccessArticle

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats

by Koki Watanabe, Daiki Asano, Hiroko Ushikubo, Akane Morita, Asami Mori, Kenji Sakamoto, Kunio Ishii and Tsutomu Nakahara

Int. J. Mol. Sci. 2021, 22(9), 4439; https://doi.org/10.3390/ijms22094439 - 23 Apr 2021

Cited by 17 | Viewed by 2509

Abstract

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its [...] Read more.

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague–Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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11 pages, 1391 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor Agonist VAF347 Impedes Retinal Pathogenesis in Diabetic Mice

by Thomas E. Zapadka, Sarah I. Lindstrom, Julia C. Batoki, Chieh A. Lee, Brooklyn E. Taylor, Scott J. Howell and Patricia R. Taylor

Int. J. Mol. Sci. 2021, 22(9), 4335; https://doi.org/10.3390/ijms22094335 - 21 Apr 2021

Cited by 13 | Viewed by 2026

Abstract

Diabetic retinopathy is the leading cause of blindness in the working-age population worldwide. Although the cause of diabetic retinopathy is multifactorial, IL-17A is a prevalent inflammatory cytokine involved in the promotion of diabetes-mediated retinal inflammation and the progression of diabetic retinopathy. The primary [...] Read more.

Diabetic retinopathy is the leading cause of blindness in the working-age population worldwide. Although the cause of diabetic retinopathy is multifactorial, IL-17A is a prevalent inflammatory cytokine involved in the promotion of diabetes-mediated retinal inflammation and the progression of diabetic retinopathy. The primary source of IL-17A is Th17 cells, which are T helper cells that have been differentiated by dendritic cells in a proinflammatory cytokine environment. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can manipulate dendritic cell maturation, halt the production of IL-6 (a proinflammatory cytokine), and suppress Th17 cell differentiation. In the current study, we examined the efficacy of an AhR agonist, VAF347, as a potential therapeutic for the onset of non-proliferative diabetic retinopathy in streptozotocin (STZ)-induced diabetic C57BL/6 mice. We determined that diabetes-mediated leukostasis, oxidative stress, and inflammation in the retina of STZ-diabetic mice were all significantly lower when treated with the AhR agonist VAF347. Furthermore, when VAF347 was subcutaneously injected into STZ-diabetic mice, retinal capillary degeneration was ameliorated, which is the hallmark of non-proliferative diabetic retinopathy in this diabetes murine model. Collectively, these findings provide evidence that the AhR agonist VAF347 could be a potentially novel therapeutic for non-proliferative diabetic retinopathy. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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19 pages, 10056 KiB

Open AccessArticle

Products of Docosahexaenoate Oxidation as Contributors to Photosensitising Properties of Retinal Lipofuscin

by Małgorzata B. Różanowska, Anna Pawlak and Bartosz Różanowski

Int. J. Mol. Sci. 2021, 22(7), 3525; https://doi.org/10.3390/ijms22073525 - 29 Mar 2021

Cited by 13 | Viewed by 2195

Abstract

Retinal lipofuscin which accumulates with age in the retinal pigment epithelium (RPE) is subjected to daily exposures to high fluxes of visible light and exhibits potent photosensitising properties; however, the molecules responsible for its photoreactivity remain unknown. Here, we demonstrate that autooxidation of [...] Read more.

Retinal lipofuscin which accumulates with age in the retinal pigment epithelium (RPE) is subjected to daily exposures to high fluxes of visible light and exhibits potent photosensitising properties; however, the molecules responsible for its photoreactivity remain unknown. Here, we demonstrate that autooxidation of docosahexaenoate (DHE) leads to the formation of products absorbing, in addition to UVB and UVA light, also visible light. The products of DHE oxidation exhibit potent photosensitising properties similar to photosensitising properties of lipofuscin, including generation of an excited triplet state with similar characteristics as the lipofuscin triplet state, and photosensitised formation of singlet oxygen and superoxide. The quantum yields of singlet oxygen and superoxide generation by oxidised DHE photoexcited with visible light are 2.4- and 3.6-fold higher, respectively, than for lipofuscin, which is consistent with the fact that lipofuscin contains some chromophores which do contribute to the absorption of light but not so much to its photosensitising properties. Importantly, the wavelength dependence of photooxidation induced by DHE oxidation products normalised to equal numbers of incident photons is also similar to that of lipofuscin—it steeply increases with decreasing wavelength. Altogether, our results demonstrate that products of DHE oxidation include potent photosensitiser(s) which are likely to contribute to lipofuscin photoreactivity. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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20 pages, 2081 KiB

Open AccessArticle

Activation of Apoptosis in a βB1-CTGF Transgenic Mouse Model

by Maximilian Weiss, Sabrina Reinehr, Ana M. Mueller-Buehl, Johanna D. Doerner, Rudolf Fuchshofer, Gesa Stute, H. Burkhard Dick and Stephanie C. Joachim

Int. J. Mol. Sci. 2021, 22(4), 1997; https://doi.org/10.3390/ijms22041997 - 17 Feb 2021

Cited by 11 | Viewed by 2138

Abstract

To reveal the pathomechanisms of glaucoma, a common cause of blindness, suitable animal models are needed. As previously shown, retinal ganglion cell and optic nerve degeneration occur in βB1-CTGF mice. Here, we aimed to determine possible apoptotic mechanisms and degeneration of different retinal [...] Read more.

To reveal the pathomechanisms of glaucoma, a common cause of blindness, suitable animal models are needed. As previously shown, retinal ganglion cell and optic nerve degeneration occur in βB1-CTGF mice. Here, we aimed to determine possible apoptotic mechanisms and degeneration of different retinal cells. Hence, retinae were processed for immunohistology (n = 5–9/group) and quantitative real-time PCR analysis (n = 5–7/group) in 5- and 10-week-old βB1-CTGF and wildtype controls. We noted significantly more cleaved caspase 3⁺ cells in βB1-CTGF retinae at 5 (p = 0.005) and 10 weeks (p = 0.02), and a significant upregulation of Casp3 and Bax/Bcl2 mRNA levels (p < 0.05). Furthermore, more terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL⁺) cells were detected in transgenic mice at 5 (p = 0.03) and 10 weeks (p = 0.02). Neurofilament H staining (p = 0.01) as well as Nefh (p = 0.02) and Tubb3 (p = 0.009) mRNA levels were significantly decreased at 10 weeks. GABAergic synapse intensity was lower at 5 weeks, while no alterations were noted at 10 weeks. The glutamatergic synapse intensity was decreased at 5 (p = 0.007) and 10 weeks (p = 0.01). No changes were observed for bipolar cells, photoreceptors, and macroglia. We conclude that apoptotic processes and synapse loss precede neuronal death in this model. This slow progression rate makes the βB1-CTGF mice a suitable model to study primary open-angle glaucoma. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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12 pages, 2454 KiB

Open AccessArticle

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage

by Gian Marco Tosi, Daniela Giustarini, Lorenzo Franci, Alberto Minetti, Francesco Imperatore, Elena Caldi, Paolo Fiorenzani, Anna Maria Aloisi, Anna Sparatore, Ranieri Rossi, Mario Chiariello, Maurizio Orlandini and Federico Galvagni

Int. J. Mol. Sci. 2021, 22(2), 600; https://doi.org/10.3390/ijms22020600 - 09 Jan 2021

Cited by 12 | Viewed by 3442

Abstract

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and [...] Read more.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats’ eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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21 pages, 2054 KiB

Open AccessArticle

Dihydrotanshinone, a Natural Diterpenoid, Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor

by Claudia Giuseppina Fresta, Giuseppe Caruso, Annamaria Fidilio, Chiara Bianca Maria Platania, Nicolò Musso, Filippo Caraci, Filippo Drago and Claudio Bucolo

Int. J. Mol. Sci. 2020, 21(23), 9305; https://doi.org/10.3390/ijms21239305 - 06 Dec 2020

Cited by 23 | Viewed by 3231

Abstract

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead [...] Read more.

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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17 pages, 3147 KiB

Open AccessArticle

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

by Lara Benning, Sabrina Reinehr, Pia Grotegut, Sandra Kuehn, Gesa Stute, H. Burkhard Dick and Stephanie C. Joachim

Int. J. Mol. Sci. 2020, 21(19), 6998; https://doi.org/10.3390/ijms21196998 - 23 Sep 2020

Cited by 4 | Viewed by 2085

Abstract

Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. [...] Read more.

Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. In an experimental autoimmune glaucoma model with systemic S100B immunization, a loss of RGCs is accompanied by a decreased synaptic signal at 28 days. Here, we aimed to study synaptic alterations in these two models. In one group, rats received a systemic S100B immunization (n = 7/group), while in the other group, S100B was injected intraocularly (n = 6–7/group). Both groups were compared to appropriate controls and investigated after 14 days. While inhibitory post-synapses remained unchanged in both models, excitatory post-synapses degenerated in animals with intraocular S100B injection (p = 0.03). Excitatory pre-synapses tendentially increased in animals with systemic S100B immunization (p = 0.08) and significantly decreased in intraocular ones (p = 0.04). Significantly more N-methyl-d-aspartate (NMDA) receptors (both p ≤ 0.04) as well as gamma-aminobutyric acid (GABA) receptors (both p < 0.03) were observed in S100B animals in both models. We assume that an upregulation of these receptors causes the interacting synapse types to degenerate. Heightened levels of excitatory pre-synapses could be explained by remodeling followed by degeneration. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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Review

Jump to: Editorial, Research

13 pages, 706 KiB

Open AccessReview

Retinal Pigment Epithelium Expressed Toll-like Receptors and Their Potential Role in Age-Related Macular Degeneration

by Alexa Klettner and Johann Roider

Int. J. Mol. Sci. 2021, 22(16), 8387; https://doi.org/10.3390/ijms22168387 - 04 Aug 2021

Cited by 13 | Viewed by 2831

Abstract

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- [...] Read more.

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- or danger-associated molecular pattern. The involvement of TLR activation in AMD is so far not understood. (2) Methods: We performed a systematic literature research, consulting the National Library of Medicine (PubMed). (3) Results: We identified 106 studies, of which 54 were included in this review. Based on these studies, the current status of TLR in AMD, the effects of TLR in RPE activation and of the interaction of TLR activated RPE with monocytic cells are given, and the potential of TLR activation in RPE as part of the AMD development is discussed. (4) Conclusion: The activation of TLR2, -3, and -4 induces a profound pro-inflammatory response in the RPE that may contribute to (long-term) inflammation by induction of pro-inflammatory cytokines, reducing RPE function and causing RPE cell degeneration, thereby potentially constantly providing new TLR ligands, which could perpetuate and, in the long run, exacerbate the inflammatory response, which may contribute to AMD development. Furthermore, the combined activation of RPE and microglia may exacerbate neurotoxic effects. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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14 pages, 646 KiB

Open AccessReview

Inherited Retinal Diseases Due to RPE65 Variants: From Genetic Diagnostic Management to Therapy

by Manar Aoun, Ilaria Passerini, Pietro Chiurazzi, Marianthi Karali, Irene De Rienzo, Giovanna Sartor, Vittoria Murro, Natalia Filimonova, Marco Seri and Sandro Banfi

Int. J. Mol. Sci. 2021, 22(13), 7207; https://doi.org/10.3390/ijms22137207 - 05 Jul 2021

Cited by 18 | Viewed by 4328

Abstract

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants [...] Read more.

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6–6% of RP and 3–16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify ‘actionable’ genotypes—i.e., genotypes that may benefit from the treatment—and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients’ access to available therapeutic options. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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29 pages, 1857 KiB

Open AccessReview

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

by Siva S.R. Iyer, Mollie K. Lagrew, Stephanie M. Tillit, Ramak Roohipourmoallai and Samuel Korntner

Int. J. Mol. Sci. 2021, 22(13), 7142; https://doi.org/10.3390/ijms22137142 - 01 Jul 2021

Cited by 9 | Viewed by 3336

Abstract

Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant [...] Read more.

Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant progress in understanding this environment and its implications in disease pathophysiology. In this review, we investigate the vitreous ecosystem in diabetic retinopathy at the molecular level. Areas of concentration include: the current level of knowledge of growth factors, cytokine and chemokine mediators, and lipid-derived metabolites in the vitreous. We discuss the molecular patho-mechanisms of diabetic retinopathy based upon current vitreous research. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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12 pages, 756 KiB

Open AccessReview

Muscarinic Acetylcholine Receptors in the Retina—Therapeutic Implications

by Yue Ruan, Andreas Patzak, Norbert Pfeiffer and Adrian Gericke

Int. J. Mol. Sci. 2021, 22(9), 4989; https://doi.org/10.3390/ijms22094989 - 08 May 2021

Cited by 12 | Viewed by 3744

Abstract

Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein-coupled receptors (GPCRs). The family of mAChRs is composed of five subtypes, M₁, M₂, M₃, M₄ and M₅, which have distinct expression patterns and functions. [...] Read more.

Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein-coupled receptors (GPCRs). The family of mAChRs is composed of five subtypes, M₁, M₂, M₃, M₄ and M₅, which have distinct expression patterns and functions. In the eye and its adnexa, mAChRs are widely expressed and exert multiple functions, such as modulation of tear secretion, regulation of pupil size, modulation of intraocular pressure, participation in cell-to-cell signaling and modula-tion of vascular diameter in the retina. Due to this variety of functions, it is reasonable to assume that abnormalities in mAChR signaling may contribute to the development of various ocular diseases. On the other hand, mAChRs may offer an attractive therapeutic target to treat ocular diseases. Thus far, non-subtype-selective mAChR ligands have been used in ophthalmology to treat dry eye disease, myopia and glaucoma. However, these drugs were shown to cause various side-effects. Thus, the use of subtype-selective ligands would be useful to circumvent this problem. In this review, we give an overview on the localization and on the functional role of mAChR subtypes in the eye and its adnexa with a special focus on the retina. Moreover, we describe the pathophysiological role of mAChRs in retinal diseases and discuss potential therapeutic approaches. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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15 pages, 745 KiB

Open AccessReview

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

by Sara Al Hussein Al Awamlh, Lauren K. Wareham, Michael L. Risner and David J. Calkins

Int. J. Mol. Sci. 2021, 22(9), 4672; https://doi.org/10.3390/ijms22094672 - 28 Apr 2021

Cited by 13 | Viewed by 3116

Abstract

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma [...] Read more.

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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11 pages, 1399 KiB

Open AccessReview

Vascular Aspects in Glaucoma: From Pathogenesis to Therapeutic Approaches

by Anna-Sophie Mursch-Edlmayr, Matthias Bolz and Clemens Strohmaier

Int. J. Mol. Sci. 2021, 22(9), 4662; https://doi.org/10.3390/ijms22094662 - 28 Apr 2021

Cited by 23 | Viewed by 3464

Abstract

Glaucomatous optic neuropathies have been regarded as diseases caused by high intraocular pressure for a long time, despite the concept of vascular glaucoma dating back to von Graefe in 1854. Since then, a tremendous amount of knowledge about the ocular vasculature has been [...] Read more.

Glaucomatous optic neuropathies have been regarded as diseases caused by high intraocular pressure for a long time, despite the concept of vascular glaucoma dating back to von Graefe in 1854. Since then, a tremendous amount of knowledge about the ocular vasculature has been gained; cohort studies have established new vascular risk factors for glaucoma as well as identifying protective measures acting on blood vessels. The knowledge about the physiology and pathophysiology of the choroidal, retinal, as well as ciliary and episcleral circulation has also advanced. Only recently have novel drugs based on that knowledge been approved for clinical use, with more to follow. This review provides an overview of the current vascular concepts in glaucoma, ranging from novel pathogenesis insights to promising therapeutic approaches, covering the supply of the optic nerve head as well as the aqueous humor production and drainage system. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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24 pages, 2485 KiB

Open AccessReview

An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials

by Wei Chiu, Ting-Yi Lin, Yun-Chia Chang, Henkie Isahwan-Ahmad Mulyadi Lai, Shen-Che Lin, Chun Ma, Aliaksandr A. Yarmishyn, Shiuan-Chen Lin, Kao-Jung Chang, Yu-Bai Chou, Chih-Chien Hsu, Tai-Chi Lin, Shih-Jen Chen, Yueh Chien, Yi-Ping Yang and De-Kuang Hwang

Int. J. Mol. Sci. 2021, 22(9), 4534; https://doi.org/10.3390/ijms22094534 - 26 Apr 2021

Cited by 45 | Viewed by 9229

Abstract

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night [...] Read more.

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye’s accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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18 pages, 745 KiB

Open AccessReview

Cannabidiol and the Canonical WNT/β-Catenin Pathway in Glaucoma

by Alexandre Vallée, Yves Lecarpentier and Jean-Noël Vallée

Int. J. Mol. Sci. 2021, 22(7), 3798; https://doi.org/10.3390/ijms22073798 - 06 Apr 2021

Cited by 19 | Viewed by 4407

Abstract

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the [...] Read more.

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway. Full article

(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)

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