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      Present and New Treatment Strategies in the Management of Glaucoma

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          Abstract

          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 restore visual function in glaucoma. The present review seeks to provide an overview of the present and new treatment strategies in the management of glaucoma. The treatment strategies are divided into current available glaucoma medications, new pressure lowering targets, prospective neuroprotective interventions, and finally possible neuroregenrative strategies.

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          Most cited references152

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          Oxidative stress and mitochondrial dysfunction in glaucoma.

          Mitochondrial dysfunction increases reactive oxygen species (ROS) production and when this overwhelms the cellular antioxidant defences, oxidative stress ensues. Oxidative stress is recognized as a common pathologic pathway in many neurodegenerative diseases. Recent reports have also demonstrated oxidative stress in ocular tissues derived from experimental glaucoma models and clinical samples. There is also accumulating evidence pointing to mitochondrial dysfunction being present in some glaucoma patients. Thus oxidative stress from mitochondrial dysfunction may also play a causal role in glaucoma. The mechanisms by which oxidative stress may induce retinal ganglion cell loss in glaucoma are not fully understood but could include direct neurotoxic effects from ROS or indirect damage from oxidative stress-induced dysfunction of glial cells. This review will consider the evidence for the presence of oxidative stress in glaucoma; the mechanisms by which oxidative stress may contribute to disease pathogenesis; and also consider therapeutic approaches that target oxidative stress as a means of protecting against optic nerve degeneration. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma.

            Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-alpha (TNF-alpha) may contribute to the disease process, although its role in vivo and its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-alpha, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-alpha injections in normal mice mimicked these effects. Conversely, an anti-TNF-alpha-neutralizing antibody or deleting the genes encoding TNF-alpha or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-alpha provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-alpha signaling or inflammation, therefore, may be helpful in treating glaucoma.
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              Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma.

              Purpose. Retrograde neurotrophic factor transport blockade has been implicated in the pathophysiology of glaucoma. Stem cell transplantation appears to ameliorate some neurodegenerative conditions in the brain and spinal cord, in part by neurotrophic factor secretion. The present study was conducted to determine whether local or systemic bone marrow-derived mesenchymal stem cell (MSC) transplantation can confer neuroprotection in a rat model of laser-induced ocular hypertensive glaucoma. Methods. MSCs were isolated from the bone marrow of adult wild-type and transgenic rats that ubiquitously express green fluorescent protein. MSCs were transplanted intravitreally 1 week before, or intravenously on the day of, ocular hypertension induction by laser photocoagulation of the trabecular meshwork. Ocular MSC localization and integration were determined by immunohistochemistry. Optic nerve damage was quantified by counting axons within optic nerve cross-sections 4 weeks after laser treatment. Results. After intravitreal transplantation, MSCs survived for at least 5 weeks. Cells were found mainly in the vitreous cavity, though a small proportion of discrete cells migrated into the host retina. Intravitreal MSC transplantation resulted in a statistically significant increase in overall RGC axon survival and a significant decrease in the rate of RGC axon loss normalized to cumulative intraocular pressure exposure. After intravenous transplantation, MSCs did not migrate to the injured eye. Intravenous transplantation had no effect on optic nerve damage. Conclusions. Local, but not systemic, transplantation of MSCs was neuroprotective in a rat glaucoma model. Autologous intravitreal transplantation of MSCs should be investigated further as a potential neuroprotective therapy for glaucoma.
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                Author and article information

                Journal
                Open Ophthalmol J
                Open Ophthalmol J
                TOOPHTJ
                The Open Ophthalmology Journal
                Bentham Open
                1874-3641
                15 May 2015
                2015
                : 9
                : 89-100
                Affiliations
                [1 ]Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Denmark
                [2 ]Department of Ophthalmology, Roskilde University Hospital, Copenhagen, Denmark
                [3 ]Center of Healthy Aging, Department of Cellular and Molecular Medicine, the Panum Institute, University of Copenhagen, Denmark
                Author notes
                [* ] Address correspondence to this author at the Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark; Tel: 0045 29807667; E-mail: mkolko@ 123456dadlnet.dk
                Article
                TOOPHTJ-9-89
                10.2174/1874364101509010089
                4460216
                b26c3362-e232-4d5b-b1d2-cd64e6023491
                © M. Kolko; Licensee Bentham Open.

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 28 March 2015
                : 30 March 2015
                : 30 March 2015
                Categories
                Article
                Suppl 1: M5

                Ophthalmology & Optometry
                glaucoma,intraocular pressure lowering drugs,neuroprotection,neuroregeneration,treatment strategies

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