Neuroprotection: A Valuable Goal in Glaucoma Management?

Glaucoma is characterized by an accelerated loss of retinal ganglion cells, as a result of damage to optic nerve axons. One factor involved in the disease process is elevated intraocular pressure (IOP) and this is the current focus of therapies. However, up to 45% of patients experience glaucoma progression despite good IOP control and partly as a result, the treatment principle of direct neuroprotection has been developed, which consists of treating optic nerve degeneration in glaucoma independently of IOP lowering. Animal models have shown the potential of this approach but there are limited clinical trial data. Brimonidine and memantine currently show promise, in terms of efficacy and side effects, among the compounds entering clinical trials. Brimonidine has been shown to have a neuroprotective effect independent of IOP lowering in humans with glaucoma, and data from a large clinical trial are being analyzed. Memantine has shown neuroprotective effects in animal models of glaucoma, and data from a clinical trial in humans are awaited.

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Neuroprotective Effects of Propylgallate Against Oxidative Stress in Retinal Ganglion Cells

10.21203/rs.3.rs-870585/v1 ◽

2021 ◽

Author(s):

Zhanjun Lu ◽

Qin Xiao ◽

Jinsong Lu ◽

Chun Tao ◽

Ruitong Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Optic Nerve ◽

Molecular Mechanism ◽

Target Genes ◽

Vision Loss ◽

Ganglion Cells ◽

Cell Model ◽

Neuroprotective Effect ◽

Neuroprotective Effects ◽

Neuroprotective Drugs

Abstract Background: Diabetic retinopathy is a group of eye diseases which result in damage to the optic nerve and vision loss, it has seriously affect peoples' health. The purpose of this study is to contrast the neuroprotective effects of curcumin, gastrodin, propylgallate, adenosine. At the same time, we preliminarily explore the molecular mechanism of protective drugs.Methods: In this study, we used 500μM H2O2 treated RGC-5 cells to induce a cellular oxidative stress model. We treated this cell model with four drug monomers: Propylgallate, Curcumin, Gastrodin and Adenosine to find drug monomers with neuroprotective effect. We used apoptosis PCR array to obtain apoptosis related genes regulated by neuroprotective drugs.Results: We found the Propylgallate treated RGC-5 cells had highest survival rate when compared to Curcumin, Gastrodin, Adenosine treated RGC-5 cells.In addition, it had lowest cell cytotoxicity and apoptotic rate when compared to Curcumin, Gastrodin, Adenosine treated RGC-5 cells.Moreover, the expression of ROS in Propylgallate treated RGC-5 cells was lowest when compared to Curcumin, Gastrodin, Adenosine treated RGC-5 cells. We found that Caspase-3, Caspase-8, and Caspase-9 are the main target genes of Propylgallate which can preliminarily explain the neuroprotective mechanism of Propylgallate against apoptosis..Conclusion: The present study revealed that the propylgallate has best neuroprotective effects, it may provide a promissing drug to prevent and improve the damage of optic nerve. In this article, we also preliminarily expounded the neuroprotective molecular mechanism of Propylgallate.

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Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

Visual Neuroscience ◽

10.1017/s0952523805225130 ◽

2005 ◽

Vol 22 (5) ◽

pp. 637-648 ◽

Cited By ~ 208

Author(s):

RICHARD T. LIBBY ◽

MICHAEL G. ANDERSON ◽

IOK-HOU PANG ◽

ZACHARY H. ROBINSON ◽

OLGA V. SAVINOVA ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cells ◽

The Elderly ◽

Nerve Degeneration ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Future Studies ◽

Age Related ◽

Iop Elevation ◽

Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

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An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical Animal Models

10.5772/intechopen.97145 ◽

2021 ◽

Author(s):

Sophie Pilkinton ◽

T.J. Hollingsworth ◽

Brian Jerkins ◽

Monica M. Jablonski

Keyword(s):

Risk Factor ◽

Intraocular Pressure ◽

Optic Nerve ◽

Animal Models ◽

Retinal Ganglion Cells ◽

Optic Nerve Head ◽

Ganglion Cells ◽

Treatment Modalities ◽

Retinal Ganglion ◽

Glaucomatous Damage

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.

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GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Scientific Reports ◽

10.1038/s41598-019-52295-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Kadri Seppa ◽

Maarja Toots ◽

Riin Reimets ◽

Toomas Jagomäe ◽

Tuuliki Koppel ◽

...

Keyword(s):

Diabetes Mellitus ◽

Optic Nerve ◽

Rat Model ◽

Receptor Agonist ◽

Neurodegenerative Disorder ◽

Ganglion Cells ◽

Neuroprotective Effect ◽

Wolfram Syndrome ◽

Retinal Ganglion ◽

Knock Out

Abstract Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.

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Animal Models of Glaucoma

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/692609 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 71

Author(s):

Rachida A. Bouhenni ◽

Jeffrey Dunmire ◽

Abby Sewell ◽

Deepak P. Edward

Keyword(s):

Optic Nerve ◽

Animal Models ◽

Visual Impairment ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Suitable Model ◽

Retinal Ganglion ◽

Ideal Model ◽

Different Types ◽

Pathophysiologic Mechanisms

Glaucoma is a heterogeneous group of disorders that progressively lead to blindness due to loss of retinal ganglion cells and damage to the optic nerve. It is a leading cause of blindness and visual impairment worldwide. Although research in the field of glaucoma is substantial, the pathophysiologic mechanisms causing the disease are not completely understood. A wide variety of animal models have been used to study glaucoma. These include monkeys, dogs, cats, rodents, and several other species. Although these models have provided valuable information about the disease, there is still no ideal model for studying glaucoma due to its complexity. In this paper we present a summary of most of the animal models that have been developed and used for the study of the different types of glaucoma, the strengths and limitations associated with each species use, and some potential criteria to develop a suitable model.

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Retinal and optic nerve degeneration in liver X receptor β knockout mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904719116 ◽

2019 ◽

Vol 116 (33) ◽

pp. 16507-16512 ◽

Cited By ~ 7

Author(s):

Xiao-yu Song ◽

Wan-fu Wu ◽

Chiara Gabbi ◽

Yu-bing Dai ◽

Mark So ◽

...

Keyword(s):

Optic Nerve ◽

Optic Neuritis ◽

Ganglion Cells ◽

Neuronal Loss ◽

Nerve Degeneration ◽

Liver X Receptors ◽

Amyloid Aβ ◽

X Receptors ◽

The Brain ◽

Optic Nerve Degeneration

The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRβ, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRβ−/− mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aβ) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aβ in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRβ−/− mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of reduction in its expression.

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Factors affecting optic nerve head biomechanics in a rat model of glaucoma

Journal of The Royal Society Interface ◽

10.1098/rsif.2019.0695 ◽

2020 ◽

Vol 17 (165) ◽

pp. 20190695 ◽

Cited By ~ 2

Author(s):

Stephen A. Schwaner ◽

Andrew J. Feola ◽

C. Ross Ethier

Keyword(s):

Optic Nerve ◽

Optic Nerve Head ◽

Ganglion Cells ◽

Disease Process ◽

Collagen Fibre ◽

Sensitivity Study ◽

Ground Substance ◽

Retinal Ganglion ◽

Factors Affecting ◽

Ganglion Cell Death

Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells, which carry vision information from the retina to the brain. Although it is well accepted that biomechanics is an important part of the glaucomatous disease process, the mechanisms by which biomechanical insult, usually due to elevated intraocular pressure (IOP), leads to retinal ganglion cell death are not understood. Rat models of glaucoma afford an opportunity for learning more about these mechanisms, but the biomechanics of the rat optic nerve head (ONH), a primary region of damage in glaucoma, are only just beginning to be characterized. In a previous study, we built finite-element models with individual-specific rat ONH geometries. Here, we developed a parametrized model of the rat ONH and used it to perform a sensitivity study to determine the influence that six geometric parameters and 13 tissue material properties have on rat optic nerve biomechanical strains due to IOP elevation. Strain magnitudes and patterns in the parametrized model generally matched those from individual-specific models, suggesting that the parametrized model sufficiently approximated rat ONH anatomy. Similar to previous studies in human eyes, we found that scleral properties were highly influential: the six parameters with highest influence on optic nerve strains were optic nerve stiffness, IOP, scleral thickness, the degree of alignment of scleral collagen fibres, scleral ground substance stiffness and the scleral collagen fibre uncrimping coefficient. We conclude that a parametrized modelling strategy is an efficient approach that allows insight into rat ONH biomechanics. Further, scleral properties are important influences on rat ONH biomechanics, and additional efforts should be made to better characterize rat scleral collagen fibre organization.

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Extrapolation of Animal Models of Optic Nerve Injury to Clinical Trial Design

Journal of Glaucoma ◽

10.1097/00061198-200402000-00001 ◽

2004 ◽

Vol 13 (1) ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Leonard A. Levin

Keyword(s):

Clinical Trial ◽

Optic Nerve ◽

Animal Models ◽

Nerve Injury ◽

Trial Design ◽

Clinical Trial Design ◽

Optic Nerve Injury

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Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1419921112 ◽

2015 ◽

Vol 112 (8) ◽

pp. 2593-2598 ◽

Cited By ~ 46

Author(s):

Ji-Jie Pang ◽

Benjamin J. Frankfort ◽

Ronald L. Gross ◽

Samuel M. Wu

Keyword(s):

Intraocular Pressure ◽

Optic Nerve ◽

Structural Damage ◽

Ganglion Cells ◽

Amacrine Cells ◽

The United States ◽

Nerve Degeneration ◽

Diagnostic Tools ◽

Inner Retina ◽

Elevated Intraocular Pressure

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.

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