scholarly journals Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Najam A. Sharif
Keyword(s):  
Optic Nerve ◽  
Anterior Chamber ◽  
Ocular Hypertension ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Surgical Techniques ◽  
Nitric Oxide Donor ◽  
Glaucomatous Optic Neuropathy ◽  
Retinal Ganglion ◽  
Outflow Pathway

Damage to the optic nerve and the death of associated retinal ganglion cells (RGCs) by elevated intraocular pressure (IOP), also known as glaucoma, is responsible for visual impairment and blindness in millions of people worldwide. The ocular hypertension (OHT) and the deleterious mechanical forces it exerts at the back of the eye, at the level of the optic nerve head/optic disc and lamina cribosa, is the only modifiable risk factor associated with glaucoma that can be treated. The elevated IOP occurs due to the inability of accumulated aqueous humor (AQH) to egress from the anterior chamber of the eye due to occlusion of the major outflow pathway, the trabecular meshwork (TM) and Schlemm’s canal (SC). Several different classes of pharmaceutical agents, surgical techniques and implantable devices have been developed to lower and control IOP. First-line drugs to promote AQH outflow via the uveoscleral outflow pathway include FP-receptor prostaglandin (PG) agonists (e.g., latanoprost, travoprost and tafluprost) and a novel non-PG EP2-receptor agonist (omidenepag isopropyl, Eybelis®). TM/SC outflow enhancing drugs are also effective ocular hypotensive agents (e.g., rho kinase inhibitors like ripasudil and netarsudil; and latanoprostene bunod, a conjugate of a nitric oxide donor and latanoprost). One of the most effective anterior chamber AQH microshunt devices is the Preserflo® microshunt which can lower IOP down to 10–13 mmHg. Other IOP-lowering drugs and devices on the horizon will be also discussed. Additionally, since elevated IOP is only one of many risk factors for development of glaucomatous optic neuropathy, a treatise of the role of inflammatory neurodegeneration of the optic nerve and retinal ganglion cells and appropriate neuroprotective strategies to mitigate this disease will also be reviewed and discussed.

scholarly journals miRNA Changes in Retinal Ganglion Cells after Optic Nerve Crush and Glaucomatous Damage

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1564
Author(s):  
Ben Mead ◽  
Alicia Kerr ◽  
Naoki Nakaya ◽  
Stanislav I. Tomarev
Keyword(s):  
Optic Nerve ◽  
Ocular Hypertension ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Optic Nerve Crush ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Rat Retina ◽  
Retinal Injury ◽  
Generation Sequencing

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.

scholarly journals Evaluation of the Effectiveness of a Chronic Ocular Hypertension Mouse Model Induced by Intracameral Injection of Cross-Linking Hydrogel

2021 ◽  
Vol 8 ◽  
Author(s):  
Junjue Chen ◽  
Jun Sun ◽  
Huan Yu ◽  
Ping Huang ◽  
Yisheng Zhong
Keyword(s):  
Intraocular Pressure ◽  
Optic Nerve ◽  
Ocular Hypertension ◽  
Retinal Ganglion Cells ◽  
Cell Activation ◽  
Ganglion Cells ◽  
Cross Linking ◽  
Control Group ◽  
Retinal Ganglion ◽  
Intracameral Injection

Background: Glaucoma is an irreversible and blinding neurodegenerative disease that is characterized by progressive loss of retinal ganglion cells. The current animal models of glaucoma fail to provide a chronic elevated intraocular pressure and cannot maintain the optical media clarity for a long time, which brings some difficulties to the study of glaucoma. Here, we developed a new chronic ocular hypertension model of mice induced by cross-linking hydrogel intracameral injection.Methods: C57BL/6J mice aged 6–8 weeks were randomly divided into the control group and the operation group. The mice of the operation group were injected with cross-linking hydrogel to induce ocular hypertension. Intraocular pressure was measured preoperatively, 3 days after surgery, and weekly until the end of the study. Flash visual evoked potential (F-VEP) was used to observe optic nerve function at different times (preoperatively and 2, 4, and 6 weeks) after chronic ocular hypertension (COH). Retinal TNF-α, IL-1β, and IL-17A protein expression were measured by western blotting in the control group and in mice at 2, 4, and 6 weeks after COH. Microglial cell activation was evaluated by immunofluorescence staining and western blotting. Apoptosis and loss of retinal ganglion cells after 2, 4, and 6 weeks of intracameral injection of cross-linking hydrogel were observed by the TUNEL assay and Brn3a protein labeling. The loss of optic nerve axons in COH mice was evaluated by neurofilament heavy polypeptide protein labeling.Results: Intracameral injection of the cross-linking hydrogel induces increased intraocular pressure (IOP) to a mean value of 19.3 ± 4.1 mmHg, which was sustained for at least 8 weeks. A significant difference in IOP was noted between COH mice and sham-operation mice (p < 0.0001). The success rate was 75%. The average amplitude of F-VEP in mice with COH was reduced (p = 0.0149, 0.0012, and 0.0009 at 2, 4, and 6 weeks after COH vs. the control group, respectively), and the average latent period in mice with COH was longer (p = 0.0290, <0.0001, and <0.0001 at 2, 4, and 6 weeks after COH vs. the control group, respectively) compared with that in the control group. TNF-α, IL-1β, IL-17A, Iba-1, and CD68 protein expression increased in COH mice. During the processing of COH, the number of microglial cells increased along with cellular morphological changes of rounder bodies and thicker processes compared with the control group. Apoptosis of retinal ganglion cells (RGCs) was clearly observed in mice at 2, 4, and 6 weeks after COH (p = 0.0061, 0.0012, <0.0001, and 0.0371 at 2, 4, and 6 weeks after COH vs. the control group, respectively). The RGC density decreased significantly in the COH mice compared with the control group (p = 0.0042, 0.0036, and <0.0001 at 2, 4, and 6 weeks after COH vs. the control group, respectively). There was a significant loss of optic nerve axons in mice after intracameral injection of cross-linking hydrogel (p = 0.0095, 0.0002, and <0.0001 at 2, 4, and 6 weeks after COH vs. the control group, respectively).Conclusions: A single intracameral injection of cross-linking hydrogel can effectively induce chronic ocular hypertension in mice, which causes progressive loss of retinal ganglion cells, increased expression levels of inflammatory cytokines and microglial cell activation, and deterioration of optic nerve function.

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 Photoreceptive retinal ganglion cells control the information rate of the optic nerve

2018 ◽  
Vol 115 (50) ◽  
pp. E11817-E11826 ◽  
Author(s):  
Nina Milosavljevic ◽  
Riccardo Storchi ◽  
Cyril G. Eleftheriou ◽  
Andrea Colins ◽  
Rasmus S. Petersen ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Information Flow ◽  
Information Transfer ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Ambient Light ◽  
Visual Responses ◽  
Light Irradiance ◽  
The Brain

Information transfer in the brain relies upon energetically expensive spiking activity of neurons. Rates of information flow should therefore be carefully optimized, but mechanisms to control this parameter are poorly understood. We address this deficit in the visual system, where ambient light (irradiance) is predictive of the amount of information reaching the eye and ask whether a neural measure of irradiance can therefore be used to proactively control information flow along the optic nerve. We first show that firing rates for the retina’s output neurons [retinal ganglion cells (RGCs)] scale with irradiance and are positively correlated with rates of information and the gain of visual responses. Irradiance modulates firing in the absence of any other visual signal confirming that this is a genuine response to changing ambient light. Irradiance-driven changes in firing are observed across the population of RGCs (including in both ON and OFF units) but are disrupted in mice lacking melanopsin [the photopigment of irradiance-coding intrinsically photosensitive RGCs (ipRGCs)] and can be induced under steady light exposure by chemogenetic activation of ipRGCs. Artificially elevating firing by chemogenetic excitation of ipRGCs is sufficient to increase information flow by increasing the gain of visual responses, indicating that enhanced firing is a cause of increased information transfer at higher irradiance. Our results establish a retinal circuitry driving changes in RGC firing as an active response to alterations in ambient light to adjust the amount of visual information transmitted to the brain.

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