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      Neuroinflammation and oxidative stress act in concert to promote neurodegeneration in the diabetic retina and optic nerve: galectin-3 participation

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          Abstract

          Diabetes is a lifelong disease characterized by glucose metabolic imbalance, in which low insulin levels or impaired insulin signaling lead to hyperglycemic state. Within 20 years of diabetes progression, 95% of patients will have diabetic retinopathy, the leading cause of visual defects in working-age people worldwide. Although diabetes is considered a microvascular disease, recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system, albeit its mechanisms are still under investigation. Neuroinflammation and oxidative stress are intrinsically related phenomena, since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases, and both pathological processes are increased in the visual system during diabetes. The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.

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          Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

          Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.
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            Retinal microglia: just bystander or target for therapy?

            Resident microglial cells can be regarded as the immunological watchdogs of the brain and the retina. They are active sensors of their neuronal microenvironment and rapidly respond to various insults with a morphological and functional transformation into reactive phagocytes. There is strong evidence from animal models and in situ analyses of human tissue that microglial reactivity is a common hallmark of various retinal degenerative and inflammatory diseases. These include rare hereditary retinopathies such as retinitis pigmentosa and X-linked juvenile retinoschisis but also comprise more common multifactorial retinal diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, and uveitis as well as neurological disorders with ocular manifestation. In this review, we describe how microglial function is kept in balance under normal conditions by cross-talk with other retinal cells and summarize how microglia respond to different forms of retinal injury. In addition, we present the concept that microglia play a key role in local regulation of complement in the retina and specify aspects of microglial aging relevant for chronic inflammatory processes in the retina. We conclude that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases of the retina.
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              NADPH oxidase in brain injury and neurodegenerative disorders

              Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Wolters Kluwer - Medknow (India )
                1673-5374
                1876-7958
                April 2020
                18 October 2019
                : 15
                : 4
                : 625-635
                Affiliations
                [1 ]Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitrio Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
                [2 ]Pólo Universitário Macaé, Unidade Integrada de Pesquisa em Produtos Bioativos e Biociências, Federal University of Rio de Janeiro, Macaé, Brazil
                [3 ]Laboratório Integrado de Morfologia, Instituto de Biodiversidade e Sustentabilidade, Núcleo de Pesquisas Ecológicas de Macaé, Federal University of Rio de Janeiro, Macaé, Brazil
                [4 ]Laboratório de Neurobiologia Celular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
                [5 ]Laboratório de Neurobiologia da Retina, Departamento de Neurobiologia, Programa de Pós-Graduação em Neurociências, Fluminense Federal University, Niterói, Brazil
                Author notes
                [* ] Correspondence to: Ana Maria Blanco Martinez, anamartinez@ 123456hucff.ufrj.br ; Karin da Costa Calaza, kcalaza@ 123456id.uff.br .

                Author contributions: All authors designed the sections of the manuscript. Abstract, optic nerve, neuroinflammatory, galectin-3 sections and Figure 3 : HRM; first draft, the oxidative damage section and Figure 2 : RCS; introduction, the retinal pathology section, Figure 1 , Table 1 and Table 2 : KCC; manuscript preparation and revision: AMBM .

                [#]

                These two authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-1199-1826
                http://orcid.org/0000-0002-0821-5730
                Article
                NRR-15-625
                10.4103/1673-5374.266910
                6975153
                31638084
                e1c3b71d-5564-436e-a7a4-39e2cf547750
                Copyright: © Neural Regeneration Research

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 26 March 2019
                : 01 April 2019
                : 11 June 2019
                Categories
                Review

                diabetes,diabetic retinopathy,galectin-3,neurodegeneration,neuroinflammation,optic nerve,oxidative stress,retina

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