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Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic...
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Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 41404

Special Issue Editors

Prof. Stanislav I. Tomarev

E-Mail Website
Guest Editor
Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Bethesda, MD 20892-0606, USA
Interests: glacoma; retinal ganglion cells; optic nerve regeneration; AMPA receptor; exosomes miRNA
Dr. Ben Mead

E-Mail Website
Guest Editor
Optometry and Vision Sciences, Cardiff University, Cardiff CF10 3AT, UK
Interests: retinal ganglion cells; exosomes/extracellular vesicles; neuroprotection; glaucoma; axon regeneration

Special Issue Information

Dear Colleagues,

The loss of retinal ganglion cells (RGCs) and their axons is a leading cause of blindness in the world and is a characteristic feature of optic neuropathies, including glaucoma, traumatic optic neuropathy and Leber’s hereditary optic neuropathy. There is growing interest in the development of RGC neuroprotective therapies for these diseases. Such therapies could be used alone or, in the case of glaucoma, in combination with intraocular pressure-lowering agents to improve RGC survival and preserve vision. There are at least 46 types of RGCs in mice, which are classified on the basis of their morphology, electrophysiological properties and gene expression patterns. The available data suggest that distinct types of RGCs may possess different sensitivities to various types of insults and may react differently to a selected neuroprotective strategy or factors.

This Special Issue aims to summarize the current knowledge on different RGC neuroprotective strategies in optic neuropathies. Most of these data were obtained using animal models and the next important step is to apply this knowledge to treatment in humans.

We look forward to your contributions.

Prof. Stanislav I. Tomarev
Dr. Ben Mead
Guest Editors

Manuscript Submission Information

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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

  • retinal ganglion cell
  • neuroprotection
  • glaucoma
  • optic nerve crush
  • animal model

Published Papers (10 papers)

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Research

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15 pages, 4366 KiB  
Article
miRNA Changes in Retinal Ganglion Cells after Optic Nerve Crush and Glaucomatous Damage
by Ben Mead, Alicia Kerr, Naoki Nakaya and Stanislav I. Tomarev
Cells 2021, 10(7), 1564; https://doi.org/10.3390/cells10071564 - 22 Jun 2021
Cited by 5 | Viewed by 2868
Abstract
The purpose of this study was to characterize the miRNA profile of purified retinal ganglion cells (RGC) from healthy and diseased rat retina. Diseased retina includes those after a traumatic optic nerve crush (ONC), and after ocular hypertension/glaucoma. Rats were separated into four [...] Read more.
The purpose of this study was to characterize the miRNA profile of purified retinal ganglion cells (RGC) from healthy and diseased rat retina. Diseased retina includes those after a traumatic optic nerve crush (ONC), and after ocular hypertension/glaucoma. Rats were separated into four groups: healthy/intact, 7 days after laser-induced ocular hypertension, 2 days after traumatic ONC, and 7 days after ONC. RGC were purified from rat retina using microbeads conjugated to CD90.1/Thy1. RNA were sequenced using Next Generation Sequencing. Over 100 miRNA were identified that were significantly different in diseased retina compared to healthy retina. Considerable differences were seen in the miRNA expression of RGC 7 days after ONC, whereas after 2 days, few changes were seen. The miRNA profiles of RGC 7 days after ONC and 7 days after ocular hypertension were similar, but discrete miRNA differences were still seen. Candidate mRNA showing different levels of expression after retinal injury were manipulated in RGC cultures using mimics/AntagomiRs. Of the five candidate miRNA identified and subsequently tested for therapeutic efficacy, miR-194 inhibitor and miR-664-2 inhibitor elicited significant RGC neuroprotection, whereas miR-181a mimic and miR-181d-5p mimic elicited significant RGC neuritogenesis. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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20 pages, 14195 KiB  
Article
Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy
by Zara Mehrabian, Yan Guo, Neil R. Miller, Amanda D. Henderson, Steven Roth and Steven L. Bernstein
Cells 2021, 10(6), 1440; https://doi.org/10.3390/cells10061440 - 09 Jun 2021
Cited by 7 | Viewed by 2313
Abstract
Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin [...] Read more.
Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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12 pages, 3560 KiB  
Article
Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies
by Vittorio Porciatti and Tsung-Han Chou
Cells 2021, 10(6), 1398; https://doi.org/10.3390/cells10061398 - 05 Jun 2021
Cited by 10 | Viewed by 2543
Abstract
As in glaucoma and other optic neuropathies cellular dysfunction often precedes cell death, the assessment of retinal ganglion cell (RGC) function represents a key outcome measure for neuroprotective strategies aimed at targeting distressed but still viable cells. RGC dysfunction can be assessed with [...] Read more.
As in glaucoma and other optic neuropathies cellular dysfunction often precedes cell death, the assessment of retinal ganglion cell (RGC) function represents a key outcome measure for neuroprotective strategies aimed at targeting distressed but still viable cells. RGC dysfunction can be assessed with the pattern electroretinogram (PERG), a sensitive measure of electrical activity of RGCs that is recorded non-invasively in human subjects and mouse models. Here, we offer a conceptual framework based on an intuitive state-transition model used for disease management in patients to identify progressive, potentially reversible stages of RGC dysfunction leading to cell death in mouse models of glaucoma and other optic neuropathies. We provide mathematical equations to describe state-transitions with a set of modifiable parameters that alter the time course and severity of state-transitions, which can be used for hypothesis testing and fitting experimental PERG data. PERG dynamics as a function of physiological stimuli are also used to differentiate phenotypic and altered RGC response dynamics, to assess susceptibility to stressors and to assess reversible dysfunction upon pharmacological treatment. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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Review

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18 pages, 1292 KiB  
Review
Immune Responses in the Glaucomatous Retina: Regulation and Dynamics
by Valery I. Shestopalov, Markus Spurlock, Oliver W. Gramlich and Markus H. Kuehn
Cells 2021, 10(8), 1973; https://doi.org/10.3390/cells10081973 - 03 Aug 2021
Cited by 20 | Viewed by 2612
Abstract
Glaucoma is a multifactorial disease resulting in progressive vision loss due to retinal ganglion cell (RGC) dysfunction and death. Early events in the pathobiology of the disease include oxidative, metabolic, or mechanical stress that acts upon RGC, causing these to rapidly release danger [...] Read more.
Glaucoma is a multifactorial disease resulting in progressive vision loss due to retinal ganglion cell (RGC) dysfunction and death. Early events in the pathobiology of the disease include oxidative, metabolic, or mechanical stress that acts upon RGC, causing these to rapidly release danger signals, including extracellular ATP, resulting in micro- and macroglial activation and neuroinflammation. Danger signaling also leads to the formation of inflammasomes in the retina that enable maturation of proinflammatory cytokines such IL-1β and IL-18. Chronic neuroinflammation can have directly damaging effects on RGC, but it also creates a proinflammatory environment and compromises the immune privilege of the retina. In particular, continuous synthesis of proinflammatory mediators such as TNFα, IL-1β, and anaphylatoxins weakens the blood–retina barrier and recruits or activates T-cells. Recent data have demonstrated that adaptive immune responses strongly exacerbate RGC loss in animal models of the disease as T-cells appear to target heat shock proteins displayed on the surface of stressed RGC to cause their apoptotic death. It is possible that dysregulation of these immune responses contributes to the continued loss of RGC in some patients. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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28 pages, 4449 KiB  
Review
The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease
by Nicole A. Muench, Sonia Patel, Margaret E. Maes, Ryan J. Donahue, Akihiro Ikeda and Robert W. Nickells
Cells 2021, 10(7), 1593; https://doi.org/10.3390/cells10071593 - 25 Jun 2021
Cited by 22 | Viewed by 4587
Abstract
The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons [...] Read more.
The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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29 pages, 5639 KiB  
Review
Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration
by Kevin Y. Zhang, Erika A. Aguzzi and Thomas V. Johnson
Cells 2021, 10(6), 1426; https://doi.org/10.3390/cells10061426 - 08 Jun 2021
Cited by 25 | Viewed by 5201
Abstract
As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. [...] Read more.
As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through exogenous RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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23 pages, 1090 KiB  
Review
Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target
by Bledi Petriti, Pete A. Williams, Gerassimos Lascaratos, Kai-Yin Chau and David F. Garway-Heath
Cells 2021, 10(6), 1402; https://doi.org/10.3390/cells10061402 - 05 Jun 2021
Cited by 18 | Viewed by 5374
Abstract
Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite [...] Read more.
Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite best treatment, suggesting that other factors confer susceptibility. Several studies indicate that mitochondrial function may underlie both susceptibility and resistance to developing glaucoma. Mitochondria meet high energy demand, in the form of ATP, that is required for the maintenance of optimum retinal ganglion cell (RGC) function. Reduced nicotinamide adenine dinucleotide (NAD+) levels have been closely correlated to mitochondrial dysfunction and have been implicated in several neurodegenerative diseases including glaucoma. NAD+ is at the centre of various metabolic reactions culminating in ATP production—essential for RGC function. In this review we present various pathways that influence the NAD+(H) redox state, affecting mitochondrial function and making RGCs susceptible to degeneration. Such disruptions of the NAD+(H) redox state are generalised and not solely induced in RGCs because of high IOP. This places the NAD+(H) redox state as a potential systemic biomarker for glaucoma susceptibility and progression; a hypothesis which may be tested in clinical trials and then translated to clinical practice. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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27 pages, 1908 KiB  
Review
Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects
by Gülgün Tezel
Cells 2021, 10(6), 1372; https://doi.org/10.3390/cells10061372 - 02 Jun 2021
Cited by 23 | Viewed by 5068
Abstract
Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths [...] Read more.
Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths with biomechanical, vascular, metabolic, oxidative, and inflammatory components. As much as intrinsic responses of RGCs themselves, divergent responses and intricate interactions of the surrounding glia also play decisive roles for the cell fate. Seen from a broad perspective, multitarget treatment strategies have a compelling pathophysiological basis to more efficiently manipulate multiple pathogenic processes at multiple injury sites in such a multifactorial neurodegenerative disease. Despite distinct molecular programs for somatic and axonal degeneration, mitochondrial dysfunction and glia-driven neuroinflammation present interdependent processes with widespread impacts in the glaucomatous retina and optic nerve. Since dysfunctional mitochondria stimulate inflammatory responses and proinflammatory mediators impair mitochondria, mitochondrial restoration may be immunomodulatory, while anti-inflammatory treatments protect mitochondria. Manipulation of these converging routes may thus allow a unified treatment strategy to protect RGC axons, somas, and synapses. This review presents an overview of recent research advancements with emphasis on potential treatment targets to achieve the best treatment efficacy to preserve visual function in glaucoma. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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18 pages, 1391 KiB  
Review
Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration
by Andrew M. Boal, Michael L. Risner, Melissa L. Cooper, Lauren K. Wareham and David J. Calkins
Cells 2021, 10(6), 1368; https://doi.org/10.3390/cells10061368 - 02 Jun 2021
Cited by 19 | Viewed by 4343
Abstract
Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. However, studies often focus on astrocytes as single-cell units. Astrocytes are densely interconnected by gap junctions that are composed primarily of [...] Read more.
Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. However, studies often focus on astrocytes as single-cell units. Astrocytes are densely interconnected by gap junctions that are composed primarily of the protein connexin-43 (Cx43) and can function as a broader network of cells. Such networks contribute to a number of important processes, including metabolite distribution and extracellular ionic buffering, and are likely to play an important role in the progression of neurodegenerative disease. This review will focus on the pro-degenerative and pro-survival influence of astrocyte Cx43 in disease progression, with a focus on the roles of gap junctions and hemichannels in the spread of degenerative stress. Finally, we will highlight the specific evidence for targeting these networks in the treatment of glaucomatous neurodegeneration and other optic neuropathies. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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19 pages, 403 KiB  
Review
Targeting Diet and Exercise for Neuroprotection and Neurorecovery in Glaucoma
by James R. Tribble, Flora Hui, Melissa Jöe, Katharina Bell, Vicki Chrysostomou, Jonathan G. Crowston and Pete A. Williams
Cells 2021, 10(2), 295; https://doi.org/10.3390/cells10020295 - 01 Feb 2021
Cited by 22 | Viewed by 5406
Abstract
Glaucoma is a leading cause of blindness worldwide. In glaucoma, a progressive dysfunction and death of retinal ganglion cells occurs, eliminating transfer of visual information to the brain. Currently, the only available therapies target the lowering of intraocular pressure, but many patients continue [...] Read more.
Glaucoma is a leading cause of blindness worldwide. In glaucoma, a progressive dysfunction and death of retinal ganglion cells occurs, eliminating transfer of visual information to the brain. Currently, the only available therapies target the lowering of intraocular pressure, but many patients continue to lose vision. Emerging pre-clinical and clinical evidence suggests that metabolic deficiencies and defects may play an important role in glaucoma pathophysiology. While pre-clinical studies in animal models have begun to mechanistically uncover these metabolic changes, some existing clinical evidence already points to potential benefits in maintaining metabolic fitness. Modifying diet and exercise can be implemented by patients as an adjunct to intraocular pressure lowering, which may be of therapeutic benefit to retinal ganglion cells in glaucoma. Full article
(This article belongs to the Special Issue Retinal Ganglion Cell Neuroprotection: Approaches to the Treatment of Optic Neuropathies)
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