scholarly journals An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David J. Mathew ◽  
Izhar Livne-Bar ◽  
Jeremy M. Sivak

AbstractGlaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study disease mechanisms and targets. Yet, current models result in IOP profiles that often do not resemble clinical glaucoma. Here we introduce a new model that results in a gradual and sustained IOP increase over time. This approach modifies a circumlimbal suture method, taking care to make the sutures ‘snug’ instead of tight, without inducing an initial IOP spike. This approach did not immediately affect IOPs, but generated gradual ocular hypertension (gOHT) as the sutures tighten over time, in comparison to loosely sutured control eyes (CON), resulting in an average 12.6 mmHg increase in IOP at 17 weeks (p < 0.001). Corresponding characterization revealed relevant retinal and optic nerve pathology, such as thinning of the retinal nerve fiber layer, decreased optokinetic response, RGC loss, and optic nerve head remodeling. Yet, angles remained open, with no evidence of inflammation. Corresponding biochemical profiling indicated significant increases in TGF-β2 and 3, and IL-1 family cytokines in gOHT optic nerve tissues compared to CON, with accompanying microglial reactivity, consistent with active tissue injury and repair mechanisms. Remarkably, this signature was absent from optic nerves following acute ocular hypertension (aOHT) associated with intentionally tightened sutures, although the resulting RGC loss was similar in both methods. These results suggest that the pattern of IOP change has an important impact on underlying pathophysiology.

2021 ◽  
Vol 8 ◽  
Author(s):  
Junjue Chen ◽  
Jun Sun ◽  
Huan Yu ◽  
Ping Huang ◽  
Yisheng Zhong

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 &lt; 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, &lt;0.0001, and &lt;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, &lt;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 &lt;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 &lt;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.


Author(s):  
Jigyasa Sahu

Aim: To describe a case of glaucoma which showed increase in optical coherence tomography (OCT) angiographic vessel densities after intraocular pressure reduction suggesting reperfusion of optic nerve. Presentation of Case: A 55 year old female with primary open angle glaucoma was taken up for trabeculectomy in view of inadequate control of intraocular pressure (IOP) despite maximal medical therapy. In addition to routine glaucoma assessment by visual fields and nerve fiber layer assessment by OCT, OCT angiographic evaluation of peripapillary vessel density was done preoperatively. Three months after trabeculectomy, her intraocular pressure decreased from 35mmHg to 14mmHg. Compared with the preoperative baseline value, the vessel density increased significantly in all quadrants after three months from surgery as demonstrated by OCT angiography. Discussion: This case report suggests that decreased optic nerve head perfusion due to high IOP can be reversed by reduction of IOP. Conclusion: Vascular parameters like angiographic vessel density can show reversible changes as decreased blood flow reinstates and thus can be better prognostic indicators than structural parameters like OCT retinal nerve fiber layer (RNFL) in glaucoma patients.


1971 ◽  
Vol 19 (2) ◽  
pp. 85-96 ◽  
Author(s):  
E. REALE ◽  
L. LUCIANO ◽  
M. SPITZNAS

In the rabbit retina acetylcholinesterase activity is localized in the perinuclear cisterna, in the cisternae of the rough surfaced endoplasmic reticulum and in the Golgi apparatus of ganglion cells and amacrine cells. The histochemical reaction is positive also in the rough surfaced endoplasmic reticulum of some horizontal cells. The highest activity is seen in the internal plexiform layer; because of artifacts caused by the diffusion of the enzyme, a clear demonstration of relation of the positivity to one or the other regular components of this layer, however, is not possible. Myelinated fibers which exhibit acetylcholinesterase activity and are most probably efferent are found in the internal plexiform layer. In the retinal nerve fiber layer and in the optic nerve only a few fibers show a positive reaction.


2021 ◽  
Author(s):  
Sophie Pilkinton ◽  
T.J. Hollingsworth ◽  
Brian Jerkins ◽  
Monica M. Jablonski

Glaucoma is a multifactorial, polygenetic disease with a shared outcome of loss of retinal ganglion cells and their axons, which ultimately results in blindness. The most common risk factor of this disease is elevated intraocular pressure (IOP), although many glaucoma patients have IOPs within the normal physiological range. Throughout disease progression, glial cells in the optic nerve head respond to glaucomatous changes, resulting in glial scar formation as a reaction to injury. This chapter overviews glaucoma as it affects humans and the quest to generate animal models of glaucoma so that we can better understand the pathophysiology of this disease and develop targeted therapies to slow or reverse glaucomatous damage. This chapter then reviews treatment modalities of glaucoma. Revealed herein is the lack of non-IOP-related modalities in the treatment of glaucoma. This finding supports the use of animal models in understanding the development of glaucoma pathophysiology and treatments.


2015 ◽  
Vol 112 (8) ◽  
pp. 2593-2598 ◽  
Author(s):  
Ji-Jie Pang ◽  
Benjamin J. Frankfort ◽  
Ronald L. Gross ◽  
Samuel M. Wu

Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3–7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.


2021 ◽  
Vol 22 (4) ◽  
pp. 1724
Author(s):  
Tsunehiko Ikeda ◽  
Kimitoshi Nakamura ◽  
Takaki Sato ◽  
Teruyo Kida ◽  
Hidehiro Oku

Dissociated optic nerve fiber layer (DONFL) appearance is characterized by dimpling of the fundus when observed after vitrectomy with the internal limiting membrane (ILM) peeling in macular diseases. However, the cause of DONFL remains largely unknown. Optical coherence tomography (OCT) findings have indicated that the nerve fiber layer (NFL) and ganglion cells are likely to have been damaged in patients with DONFL appearance. Since DONFL appearance occurs at a certain postoperative period, it is unlikely to be retinal damage directly caused by ILM peeling because apoptosis occurs at a certain period after tissue damage and/or injury. However, it may be due to ILM peeling-induced apoptosis in the retinal tissue. Anoikis is a type of apoptosis that occurs in anchorage-dependent cells upon detachment of those cells from the surrounding extracellular matrix (i.e., the loss of cell anchorage). The anoikis-related proteins βA3/A1 crystallin and E-cadherin are reportedly expressed in retinal ganglion cells. Thus, we theorize that one possible cause of DONFL appearance is ILM peeling-induced anoikis in retinal ganglion cells.


2021 ◽  
Vol 12 ◽  
Author(s):  
Najam A. Sharif

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.


2003 ◽  
Vol 127 (10) ◽  
pp. 1314-1319 ◽  
Author(s):  
Luigi Giarelli ◽  
Giovanni Falconieri ◽  
J. Douglas Cameron ◽  
Alfred M. Pheley

Abstract Context.—Schnabel cavernous degeneration is a histologic finding originally attributed to glaucoma; however, its cause and significance have been controversial. Objective.—To determine the basic cause of the formation of cavernous spaces in the proximal optic nerve and its clinical significance. Methods.—A retrospective analysis of 4500 autopsy eyes processed for histologic evaluation between 1967 and 1991. Results.—Ninety-three (2.1% of eyes examined) cases of Schnabel cavernous optic atrophy were identified. The majority of the eyes were from women (81%). The mean age of the entire group was 88 years (reference range, 54–103 years). Severe vascular anomalies were present in 75% of the individuals. Cavernous degeneration was unilateral in 82% of the cases. Loss of ganglion cells and nerve fiber layer consistent with glaucoma was found in 23.7% of the individuals. Clinical information was available for 15 individuals (16%). Half of them were thought to have some clinical optic nerve damage; in the remainder, no specific optic disc abnormalities were noted. Histologic findings of arteriolosclerosis in the optic nerve circulation were common. The prevalence of glaucoma was low. Conclusions.—Schnabel cavernous optic atrophy appears to be a unilateral condition of elderly women with systemic vascular disease and few characteristic ocular features. Our data indicate that a chronic vascular occlusive disease of the proximal optic nerve is more involved in cavernous atrophic pathogenesis than is a sustained increase of intraocular pressure.


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