Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention (original) (raw)

Current Trends in Glaucoma: What about Neuroprotection?

Glaucoma is an optic neuropathy, considered as the second leading cause of blindness worldwide. Glaucoma is characterized by selective death of retinal ganglion cells (RGC) and a progressive loss of vision. Elevated intraocular pressure (IOP) is one of the most important risk factors for developing glaucoma, so we mainly focus on lowering IOP to arrest the progression of glaucoma. However, many patients continue to demonstrate a clinically downhill course despite the control of initially raised IOP. In fact, some patients develop what is called Normal Tension Glaucoma, not associated to an increased IOP. This emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high intraocular pressure (IOP) and vascular insufficiency in the optic nerve head are only risk factors for the development of glaucoma, and are not the only target for the treatment of glaucoma. The reason is that the process of RGC death is thought to be biphasic, and the primary injury is followed by a slower secondary degeneration related to a noxious environment surrounding the apoptotic cells. This environment is characterized by changes in the extra-cellular ionic concentrations, increased amounts of free radicals, neurotrophins depletion and increased glutamate induced excitotoxicity due to high extra-cellular glutamate levels, which binds

Innovations and revolutions in reducing retinal ganglion cell loss in glaucoma

Expert Review of Ophthalmology, 2020

Introduction Glaucoma remains the leading cause of irreversible blindness. Although the loss of retinal ganglion cells (RGCs) is an established hallmark of glaucoma, reduction of intraocular pressure (IOP) is a widely used evidence-based management approach, even in normotensive patients. However, despite optimal pressure control, some patients progress to lose vision. Areas covered This review provides a summary of the latest methods aimed at reducing RGC loss with the objective of preserving vision, categorized by the mechanism of action. We discuss both the newest ways in which IOP can be reduced, alongside ‘pressure-independent’ pharmacological therapies and developments in bioengineering. The conducted PubMed search included the terms: ‘glaucoma pathophysiology,’ ‘IOP-lowering agents,’ ‘retinal ganglion cell apoptosis,’ ‘neuroprotection,’ ‘stem cells,’ ‘imaging.’ Expert opinion With many agents failing to successfully translate into clinical use, further understanding of the un...

Neuroprotection in Glaucoma: A Paradigm Shift

Glaucoma is a complex, multifactorial eye disease characterized by loss of retinal ganglion cells (RGCs) and their axons, leading to progressive, irreversible optic neuropathy and visual field loss. The weight of current clinical evidence, therefore, suggests that a novel approach, independent of intraocular pressure (IOP) lowering, aimed at protecting the retinal ganglion cells and optic nerve head from damage is most desirable. The underlying pathophysiologic basis of glaucoma may be attributed to neurodegenerative changes involving multiple pathways and diverse mechanisms. These pathways are potential targets for multifunctional drugs aimed at neuroprotection against glaucoma. The most rational therapeutic approach in reversing or preventing retinal ganglion cell death entails simultaneously targeting these multiple pathways. Hence, the idea of neuroprotection remains a novel therapeutic and promising prospect in the management of glaucoma. This review paper examines current issues on the pathophysiologic basis, potential targets and novel therapeutic approach to neuroprotection in glaucoma.

Glaucoma: the retina and beyond

Acta neuropathologica, 2016

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of...

Current perspective of neuroprotection and glaucoma

Clinical Ophthalmology, 2015

Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment.

Present and New Treatment Strategies in the Management of Glaucoma

The open ophthalmology journal, 2015

Glaucoma is a neurodegenerative disease characterized by retinal ganglion cell (RGC) death and axonal loss. It remains a major cause of blindness worldwide. All current modalities of treatment are focused on lowering intraocular pressure (IOP), and it is evident that increased IOP is an important risk factor for progression of the disease. However, it is clear that a significant number of glaucoma patients show disease progression despite of pressure lowering treatments. Much attention has been given to the development of neuroprotective treatment strategies, but the identification of such has been hampered by lack of understanding of the etiology of glaucoma. Hence, in spite of many attempts no neuroprotective drug has yet been clinically approved. Even though neuroprotection is without doubt an important treatment strategy, many glaucoma subjects are diagnosed after substantial loss of RGCs. In this matter, recent approaches aim to rescue RGCs and regenerate axons in order to rest...

The molecular basis of retinal ganglion cell death in glaucoma

Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death. In recent years, there has been an exponential increase in valuable information regarding the molecular basis of RGC death stemming from animal models of acute and chronic optic nerve injury as well as experimental glaucoma. The emerging landscape is complex and points at a variety of molecular signals e acting alone or in cooperation e to promote RGC death. These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochon-drial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity. Collectively, this body of work has considerably updated and expanded our view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection.

Neuroprotection in Glaucoma: Old and New Promising Treatments

Advances in Pharmacological Sciences, 2017

Glaucoma is a major global cause of blindness, but the molecular mechanisms responsible for the neurodegenerative damage are not clear. Undoubtedly, the high intraocular pressure (IOP) and the secondary ischemic and mechanical damage of the optic nerve have a crucial role in retinal ganglion cell (RGC) death. Several studies specifically analyzed the events that lead to nerve fiber layer thinning, showing the importance of both intra- and extracellular factors. In parallel, many neuroprotective substances have been tested for their efficacy and safety in hindering the negative effects that lead to RGC death. New formulations of these compounds, also suitable for chronic oral administration, are likely to be used in clinical practice in the future along with conventional therapies, in order to control the progression of the visual impairment due to primary open-angle glaucoma (POAG). This review illustrates some of these old and new promising agents for the adjuvant treatment of POAG...

Potential Neuroprotective Therapy for Glaucoma

Arquivos Brasileiros De Oftalmologia, 1999

Glaucoma is often associated with high intraocular pressure (IOP), but continues to progress even after normalization of IOP. We have suggested that such progression is at least partly doe to delayed degeneration of spared neurons by their exposure to the degenerative milieu created by degenerating neurons, the primary victims of high IOP. The extent of delayed (secondary) degeneration is apparently a function of the severity of the primary insult, which affects the levei of toxicity mediators and the spared neurons' susceptibility to them. We developed a model of adult rat partial optic nerve lesion to quantify the extent of primary and secondary damage, respectively, and find out why patients with severe pre-existing damage are more prone to deterioration than patients without pre-existing visual loss. The model also screens compounds for neuroprotective efficacy. Our findings support our suggestion that glaucoma therapy should consist of a combination of neuroprotection and ocular hypotensive therapy.

Pathophysiology of primary open-angle glaucoma from a neuroinflammatory and neurotoxicity perspective: a review of the literature

International Ophthalmology, 2017

Purpose Glaucoma is the leading cause of blindness in humans, affecting 2% of the population. This disorder can be classified into various types including primary, secondary, glaucoma with angle closure and with open angle. The prevalence of distinct types of glaucoma differs for each particular region of the world. One of the most common types of this disease is primary open-angle glaucoma (POAG), which is a complex inherited disorder characterized by progressive retinal ganglion cell death, optic nerve head excavation and visual field loss. Nowadays, POAG is considered an optic neuropathy, while intraocular pressure is proposed to play a fundamental role in its pathophysiology and especially in optic disk damage. However, the exact mechanism of optic nerve head damage remains a topic of debate. This literature review aims to bring together the information on the pathophysiology of primary open-angle glaucoma, particularly focusing on neuroinflammatory mechanisms leading to the death of the retinal ganglion cell. Methods A literature search was done on PubMed using key words including primary open-angle glaucoma, retinal ganglion cells, Müller cells, glutamate, glial cells, ischemia, hypoxia, exitotoxicity, neuroinflammation, axotomy and neurotrophic factors. The literature was reviewed to collect the information published about the pathophysiologic mechanisms of RGC death in the POAG, from a neuroinflammatory and neurotoxicity perspective. Results Proposed mechanisms for glaucomatous damage are a result of pressure in RGC followed by ischemia, hypoxia of the ONH, and consequently death due to glutamate-induced excitotoxicity, deprivation of energy and oxygen, increase in levels of inflammatory mediators and alteration of trophic factors flow. These events lead to blockage of anterograde and retrograde axonal transport with ensuing axotomy and eventually blindness. Conclusions The damage to ganglion cells and eventually glaucomatous injury can occur via various mechanisms including baric trauma, ischemia and impact of metabolic toxins, which triggers an inflammatory process and secondary degeneration in the ONH.