scholarly journals Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1426
Author(s):  
Kevin Y. Zhang ◽  
Erika A. Aguzzi ◽  
Thomas V. Johnson
Keyword(s):  
Optic Nerve ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Functional Integration ◽  
Experimental Models ◽  
Bipolar Cells ◽  
Retinal Ganglion ◽  
Current State ◽  
Collective Effort ◽  
The Central Nervous System

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.

scholarly journals Targeting Oxidative Stress for Treatment of Glaucoma and Optic Neuritis

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Atsuko Kimura ◽  
Kazuhiko Namekata ◽  
Xiaoli Guo ◽  
Takahiko Noro ◽  
Chikako Harada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Optic Nerve ◽  
Optic Neuritis ◽  
Vision Loss ◽  
Demyelinating Disease ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Progressive Degeneration ◽  
Elevated Intraocular Pressure ◽  
The Central Nervous System

Glaucoma is a neurodegenerative disease of the eye and it is one of the leading causes of blindness. Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons, namely, the optic nerve, usually associated with elevated intraocular pressure (IOP). Current glaucoma therapies target reduction of IOP, but since RGC death is the cause of irreversible vision loss, neuroprotection may be an effective strategy for glaucoma treatment. One of the risk factors for glaucoma is increased oxidative stress, and drugs with antioxidative properties including valproic acid and spermidine, as well as inhibition of apoptosis signal-regulating kinase 1, an enzyme that is involved in oxidative stress, have been reported to prevent glaucomatous retinal degeneration in mouse models of glaucoma. Optic neuritis is a demyelinating inflammation of the optic nerve that presents with visual impairment and it is commonly associated with multiple sclerosis, a chronic demyelinating disease of the central nervous system. Although steroids are commonly used for treatment of optic neuritis, reduction of oxidative stress by approaches such as gene therapy is effective in ameliorating optic nerve demyelination in preclinical studies. In this review, we discuss oxidative stress as a therapeutic target for glaucoma and optic neuritis.

scholarly journals Demyelination of the Optic Nerve: An Underlying Factor in Glaucoma?

2021 ◽  
Vol 13 ◽  
Author(s):  
Jingfei Xue ◽  
Yingting Zhu ◽  
Zhe Liu ◽  
Jicheng Lin ◽  
Yangjiani Li ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Ganglion Cells ◽  
Neuronal Degeneration ◽  
Retinal Ganglion ◽  
Progressive Degeneration ◽  
Treatment Plans ◽  
The Central Nervous System ◽  
The Relationship

Neurodegenerative disorders are characterized by typical neuronal degeneration and axonal loss in the central nervous system (CNS). Demyelination occurs when myelin or oligodendrocytes experience damage. Pathological changes in demyelination contribute to neurodegenerative diseases and worsen clinical symptoms during disease progression. Glaucoma is a neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and the optic nerve. Since it is not yet well understood, we hypothesized that demyelination could play a significant role in glaucoma. Therefore, this study started with the morphological and functional manifestations of demyelination in the CNS. Then, we discussed the main mechanisms of demyelination in terms of oxidative stress, mitochondrial damage, and immuno-inflammatory responses. Finally, we summarized the existing research on the relationship between optic nerve demyelination and glaucoma, aiming to inspire effective treatment plans for glaucoma in the future.

scholarly journals Foveate vision in deep–sea teleosts: a comparison of primary visual and olfactory inputs

2000 ◽  
Vol 355 (1401) ◽  
pp. 1315-1320 ◽  
Author(s):  
Shaun P. Collin ◽  
Darren J. Lloyd ◽  
Hans–Joachim Wagner
Keyword(s):  
Optic Nerve ◽  
Deep Sea ◽  
Ganglion Cells ◽  
Relative Size ◽  
Olfactory Nerve ◽  
Resolving Power ◽  
Retinal Ganglion ◽  
Foveal Vision ◽  
Bias Ratio ◽  
The Central Nervous System

The relative importance of vision in a foveate group of alepocephalid teleosts is examined in the context of a deep–sea habitat beyond the penetration limits of sunlight. The large eyes of Conocara spp. possess deep convexiclivate foveae lined with Müller cells comprising radial shafts of intermediate filaments and horizontal processes. Photoreceptor cell (171.8 × 10 3 rods mm −2 ) and retinal ganglion cell (11.9 × 10 3 cells mm −2 ) densities peak within the foveal clivus and the perifoveal slopes, respectively, with a centro–peripheral gradient between 3:1 (photoreceptors) and over 20:1 (ganglion cells). The marked increase in retinal sampling localized in temporal retina, coupled with a high summation ratio (13:1), suggest that foveal vision optimizes both spatial resolving power and sensitivity in the binocular frontal visual field. The elongated optic nerve head is comprised of over 500 optic papillae, which join at the embryonic fissure to form a thin nervous sheet behind the eye. The optic nerve is divided into two axonal bundles; one receiving input from the fovea (only unmyelinated axons) and the other from non–specialized retinal regions (25% of axons are myelinated), both of which appear to be separated as they reach the visual centres of the central nervous system. Comparison of the number of primary (first–order) axonal pathways for the visual (a total of 63.4 × 10 6 rod photoreceptors) and olfactory (a total of 15.24 × 10 5 olfactory nerve axons) inputs shows a marked visual bias (ratio of 41:1). Coupled with the relative size of the optic tecta (44.0 mm 3 ) and olfactory bulbs (0.9 mm 3 ), vision appears to play a major role in the survival of these deep–sea teleosts and emphasizes that ecological and behavioural strategies account for significant variation in sensory brain structure.

scholarly journals Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Elena G. Sergeeva ◽  
Paul A. Rosenberg ◽  
Larry I. Benowitz
Keyword(s):  
Optic Nerve ◽  
Visual Information ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Inflammatory Cells ◽  
Retinal Ganglion ◽  
Ability To Regenerate ◽  
Mature Neurons ◽  
The Central Nervous System ◽  
Extracellular Environment

Visual information is conveyed from the eye to the brain through the axons of retinal ganglion cells (RGCs) that course through the optic nerve and synapse onto neurons in multiple subcortical visual relay areas. RGCs cannot regenerate their axons once they are damaged, similar to most mature neurons in the central nervous system (CNS), and soon undergo cell death. These phenomena of neurodegeneration and regenerative failure are widely viewed as being determined by cell-intrinsic mechanisms within RGCs or to be influenced by the extracellular environment, including glial or inflammatory cells. However, a new concept is emerging that the death or survival of RGCs and their ability to regenerate axons are also influenced by the complex circuitry of the retina and that the activation of a multicellular signaling cascade involving changes in inhibitory interneurons – the amacrine cells (AC) – contributes to the fate of RGCs. Here, we review our current understanding of the role that interneurons play in cell survival and axon regeneration after optic nerve injury.

Gene Therapy Strategies for Glaucomatous Neurodegeneration

2021 ◽  
Vol 21 ◽  
Author(s):  
Rafael Lani-Louzada ◽  
Mariana Santana Dias ◽  
Rafael Linden ◽  
Vinicius de Toledo Ribas ◽  
Hilda Petrs-Silva
Keyword(s):  
Gene Therapy ◽  
Intraocular Pressure ◽  
Retinal Ganglion Cells ◽  
Viral Vectors ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Experimental Studies ◽  
Current Treatment ◽  
Experimental Models ◽  
Retinal Ganglion

: Glaucoma leads to irreversible vision loss and current therapeutic strategies are often insufficient to prevent the progression of the disease and consequent blindness. Elevated intraocular pressure is an important risk factor, but not required for the progression of glaucomatous neurodegeneration. The demise of retinal ganglion cells represents the final common pathway of glaucomatous vision loss. Still, lifelong control of intraocular pressure is the only current treatment to prevent severe vision loss, although it frequently fails despite best practices. This scenario calls for the development of neuroprotective and pro-regenerative therapies targeting the retinal ganglion cells as well as the optic nerve. Several experimental studies have shown the potential of gene modulation as a tool for neuroprotection and regeneration. In this context, gene therapy represents an attractive approach as persistent treatment for glaucoma. Viral vectors engineered to promote overexpression of a broad range of cellular factors have been shown to protect retinal ganglion cells and/or promote axonal regeneration in experimental models. Here, we review the mechanisms involved in glaucomatous neurodegeneration and regeneration in the central nervous system. Then, we point out current limitations of gene therapy platforms and review a myriad of studies that use viral vectors to manipulate genes in retinal ganglion cells, as a strategy to promote neuroprotection and regeneration. Finally, we address the potential of combining neuroprotective and regenerative gene therapies as an approach to glaucomatous neurodegeneration.

scholarly journals Harnessing Astrocytes and Müller Glial Cells in the Retina for Survival and Regeneration of Retinal Ganglion Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1339
Author(s):  
Hyung-Suk Yoo ◽  
Ushananthini Shanmugalingam ◽  
Patrice D. Smith
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Reactive Gliosis ◽  
Retinal Ganglion ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Retinal Degenerative Diseases

Astrocytes have been associated with the failure of axon regeneration in the central nervous system (CNS), as it undergoes reactive gliosis in response to damages to the CNS and functions as a chemical and physical barrier to axon regeneration. However, beneficial roles of astrocytes have been extensively studied in the spinal cord over the years, and a growing body of evidence now suggests that inducing astrocytes to become more growth-supportive can promote axon regeneration after spinal cord injury (SCI). In retina, astrocytes and Müller cells are known to undergo reactive gliosis after damage to retina and/or optic nerve and are hypothesized to be either detrimental or beneficial to survival and axon regeneration of retinal ganglion cells (RGCs). Whether they can be induced to become more growth-supportive after retinal and optic nerve injury has yet to be determined. In this review, we pinpoint the potential molecular pathways involved in the induction of growth-supportive astrocytes in the spinal cord and suggest that stimulating the activation of these pathways in the retina could represent a new therapeutic approach to promoting survival and axon regeneration of RGCs in retinal degenerative diseases.

scholarly journals Rod bipolar cells dysfunction occurs before ganglion cells loss in excitotoxin-damaged mouse retina

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Yumeng Shen ◽  
Xue Luo ◽  
Shiliang Liu ◽  
Ying Shen ◽  
Scott Nawy ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Experimental Models ◽  
Bipolar Cells ◽  
Diagnostic Tools ◽  
Mouse Retina ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Retinal Ganglion ◽  
Rod Bipolar Cells

AbstractProgressive degeneration of retinal ganglion cells (RGCs) will cause a blinding disease. Most of the study is focusing on the RGCs itself. In this study, we demonstrate a decline of the presynaptic rod bipolar cells (RBCs) response precedes RGCs loss and a decrease of protein kinase Cα (PKCα) protein expression in RBCs dendrites, using whole-cell voltage-clamp, electroretinography (ERG) measurements, immunostaining and co-immunoprecipitation. We present evidence showing that N-methyl D-aspartate receptor subtype 2B (NR2B)/protein interacting with C kinase 1 (PICK1)-dependent degradation of PKCα protein in RBCs contributes to RBCs functional loss. Mechanistically, NR2B forms a complex with PKCα and PICK1 to promote the degradation of PKCα in a phosphorylation- and proteasome-dependent manner. Similar deficits in PKCα expression and response sensitivity were observed in acute ocular hypertension and optic never crush models. In conclusion, we find that three separate experimental models of neurodegeneration, often used to specifically target RGCs, disrupt RBCs function prior to the loss of RGCs. Our findings provide useful information for developing new diagnostic tools and treatments for retinal ganglion cells degeneration disease.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

scholarly journals Cytotoxic and anti-excitotoxic effects of selected plant and algal extracts using COMET and cell viability assays

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abeer Aldbass ◽  
Musarat Amina ◽  
Nawal M. Al Musayeib ◽  
Ramesa Shafi Bhat ◽  
Sara Al-Rashed ◽  
...  
Keyword(s):  
Cell Viability ◽  
Plant Extracts ◽  
Ganglion Cells ◽  
Cell Damage ◽  
Primary Cultures ◽  
Glutamate Excitotoxicity ◽  
Retinal Ganglion ◽  
Gradual Loss ◽  
The Central Nervous System ◽  
Mtt Assays

AbstractExcess glutamate in the central nervous system may be a major cause of neurodegenerative diseases with gradual loss and dysfunction of neurons. Primary or secondary metabolites from medicinal plants and algae show potential for treatment of glutamate-induced excitotoxicity. Three plant extracts were evaluated for impact on glutamate excitotoxicity-induced in primary cultures of retinal ganglion cells (RGC). These cells were treated separately in seven groups: control; Plicosepalus. curviflorus treated; Saussurea lappa treated; Cladophora glomerate treated. Cells were treated independently with 5, 10, 50, or 100 µg/ml of extracts of plant or alga material, respectively, for 2 h. Glutamate-treated cells (48 h with 5, 10, 50, or 100 µM glutamate); and P. curviflorus/glutamate; S. lappa/glutamate; C. glomerata/glutamate [pretreatment with extract for 2 h (50 and 100 µg/ml) before glutamate treatment with 100 µM for 48 h]. Comet and MTT assays were used to assess cell damage and cell viability. The number of viable cells fell significantly after glutamate exposure. Exposure to plant extracts caused no notable effect of viability. All tested plants extracts showed a protective effect against glutamate excitotoxicity-induced RGC death. Use of these extracts for neurological conditions related to excitotoxicity and oxidative stress might prove beneficial.

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