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      Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

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          Abstract

          Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

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          Most cited references65

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          The impact of ocular blood flow in glaucoma.

          Two principal theories for the pathogenesis of glaucomatous optic neuropathy (GON) have been described--a mechanical and a vascular theory. Both have been defended by various research groups over the past 150 years. According to the mechanical theory, increased intraocular pressure (IOP) causes stretching of the laminar beams and damage to retinal ganglion cell axons. The vascular theory of glaucoma considers GON as a consequence of insufficient blood supply due to either increased IOP or other risk factors reducing ocular blood flow (OBF). A number of conditions such as congenital glaucoma, angle-closure glaucoma or secondary glaucomas clearly show that increased IOP is sufficient to lead to GON. However, a number of observations such as the existence of normal-tension glaucoma cannot be satisfactorily explained by a pressure theory alone. Indeed, the vast majority of published studies dealing with blood flow report a reduced ocular perfusion in glaucoma patients compared with normal subjects. The fact that the reduction of OBF often precedes the damage and blood flow can also be reduced in other parts of the body of glaucoma patients, indicate that the hemodynamic alterations may at least partially be primary. The major cause of this reduction is not atherosclerosis, but rather a vascular dysregulation, leading to both low perfusion pressure and insufficient autoregulation. This in turn may lead to unstable ocular perfusion and thereby to ischemia and reperfusion damage. This review discusses the potential role of OBF in glaucoma and how a disturbance of OBF could increase the optic nerve's sensitivity to IOP.
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            The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina.

            With the advent of genome-wide analyses, it is becoming evident that a large number of noncoding RNAs (ncRNAs) are expressed in vertebrates. However, of the thousands of ncRNAs identified, the functions of relatively few have been established. In a screen for genes upregulated by taurine in developing retinal cells, we identified a gene that appears to be a ncRNA. Taurine Upregulated Gene 1 (TUG1) is a spliced, polyadenylated RNA that does not encode any open reading frame greater than 82 amino acids in its full-length, 6.7 kilobase (kb) RNA sequence. Analyses of Northern blots and in situ hybridization revealed that TUG1 is expressed in the developing retina and brain, as well as in adult tissues. In the newborn retina, knockdown of TUG1 with RNA interference (RNAi) resulted in malformed or nonexistent outer segments of transfected photoreceptors. Immunofluorescent staining and microarray analyses suggested that this loss of proper photoreceptor differentiation is a result of the disregulation of photoreceptor gene expression. A function for a newly identified ncRNA, TUG1, has been established. TUG1 is necessary for the proper formation of photoreceptors in the developing rodent retina.
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              Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas.

              To characterize Brn3a expression in adult albino rat retinal ganglion cells (RGCs) in naïve animals and in animals subjected to complete intraorbital optic nerve transection (IONT) or crush (IONC). Rats were divided into three groups, naïve, IONT, and IONC. Two-, 5-, 9-, or 14-day postlesion (dpl) retinas were examined for immunoreactivity for Brn3a. Before the injury, the RGCs were labeled with Fluorogold (FG; Fluorochrome, Corp. Denver, CO). Brn3a retinal expression was also determined by Western blot analysis. The proportion of RGCs double labeled with Brn3a and FG was determined in radial sections. The temporal course of reduction in Brn3a(+) RGCs and FG(+) RGCs induced by IONC or IONT was assessed by quantifying, in the same wholemounts, the number of surviving FG-labeled RGCs and Brn3a(+)RGCs at the mentioned time points. The total number of FG(+)RGCs was automatically counted in naïve and injured retinas (2 and 5 dpl) or estimated by manual quantification in retinas processed at 9 and 14 dpl. All Brn3a immunopositive RGCs were counted using an automatic routine specifically developed for this purpose. This protocol allowed, as well, the investigation of the spatial distribution of these neurons. Brn3a(+) cells were only present in the ganglion cell layer and showed a spatial distribution comparable to that of FG(+) cells. In the naïve retinal wholemounts the mean (mean +/- SEM; n = 14) total number of FG(+)RGCs and Brn3a(+)RGCs was 80,251 +/- 2,210 and 83,449 +/- 4,541, respectively. Whereas in the radial sections, 92.2% of the FG(+)RGCs were also Brn3a(+), 4.4% of the RGCs were Brn3a(+)FG(-) and 3.4% were FG(+)Brn3a(-). Brn3a expression pattern was maintained in injured RGCs. The temporal course of Brn3a(+)RGC and FG(+)RGC loss induced by IONC or IONT followed a similar trend, but Brn3a(+)RGCs loss was detected earlier than that of FG(+)RGCs. Independent of the marker used to detect the RGCs, it was observed that their loss was quicker and more severe after IONT than after IONC. Brn3a can be used as a reliable, efficient ex vivo marker to identify and quantify RGCs in control and optic nerve-injured retinas.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                24 October 2012
                : 7
                : 10
                : e42017
                Affiliations
                [1 ]Institut National de la Santé et de la Recherche Médicale UMR 968, Institut de la Vision, Paris, France
                [2 ]L’université Pierre et Marie Curie, Université Paris 06, UMR_S 968, Institut de la Vision, Paris, France
                [3 ]Centre National de la Recherche Scientifique UMR7210, Institut de la Vision, Paris, France
                [4 ]Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France
                [5 ]Institut des systèmes intelligents et robotique, l’université Pierre et Marie Curie, Paris, France
                [6 ]Centre National de la Recherche Scientifique UMR7222, Paris, France
                [7 ]Institute of Ophthalmology, University College of London, London, United Kingdom
                [8 ]Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
                [9 ]French Academy of Sciences, Paris, France
                Faculty of Medicine University of Leipzig, Germany
                Author notes

                Competing Interests: JAS, TL, MS and SP were consultants at Fovea Pharma, which supported the study. A patent has been filed on the data, United States Patent Application 20120027723. The present invention relates to taurine or taurine-like substances for the prevention and treatment of a disease associated with retinal ganglion cell degeneration. More particularly the invention relates to a substance selected from the group consisting of taurine, a taurine precursor, a taurine metabolite, a taurine derivative, a taurine analog and a substance required for the taurine biosynthesis for the prevention and treatment of a disease associated with retinal ganglion cell degeneration. There are no other patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: NF L. Cadetti HL JM APB FJ TL RB JAS SP. Performed the experiments: NF L. Cadetti HL JM ED JD DP VF L. Chicaud MS II. Analyzed the data: NF L. Cadetti HL APB ED DP SF. Contributed reagents/materials/analysis tools: NF L. Cadetti APB MS SF FJ SP. Wrote the paper: NF L. Cadetti RB JAS SP.

                Article
                PONE-D-12-08563
                10.1371/journal.pone.0042017
                3480351
                23115615
                58a7e020-6b33-4e65-8e2a-6da4dc6e7450
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 March 2012
                : 29 June 2012
                Page count
                Pages: 11
                Funding
                This work was supported by Institut National de la Sant? et de la Recherche M?dicale, Université Pierre et Marie Curie (Paris VI), the Fondation Ophtalmologique A. de Rothschild (Paris), Agence Nationale pour la Recherche (ANR: GLAUCOME), the European Community contrat TREATRUSH (n° HEALTH-F2-2010-242013), the Fédération des Aveugles de France, IRRP, the city of Paris, the Regional Council of Ile-de-France. L. Cadetti and NF received postdoctoral fellowships from the Fondation pour la Recherche Médicale, JM a doctoral fellowship from the Fundação para a Ciência e a Tecnologia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Drug Discovery
                Biotechnology
                Drug Discovery
                Molecular Cell Biology
                Cell Death
                Neuroscience
                Sensory Systems
                Visual System
                Neurobiology of Disease and Regeneration
                Medicine
                Drugs and Devices
                Drug Research and Development
                Drug Discovery
                Neuropharmacology
                Ophthalmology
                Retinal Disorders

                Uncategorized
                Uncategorized

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