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      NADPH oxidase in brain injury and neurodegenerative disorders

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          Abstract

          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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          Most cited references337

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          Multiple Sclerosis

          New England Journal of Medicine, 343(13), 938-952
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            A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

            Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometers within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown. Due to their fast diffusion and versatile biological activities, reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are interesting candidates for wound-to-leukocyte signalling. We probed the role of H2O2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H2O2 sensor1. This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting ∼3 min after wounding and peaking at ∼20 min, which extended ∼100−200 μm into the tail fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by Dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role.
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              Overview and findings from the rush Memory and Aging Project.

              The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and risk of Alzheimer's disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: (1) the relation of motor function to cognition, disability, and death; (2) the relation of risk factors to cognitive and motor outcomes, disability and death; (3) the relation of neuropathologic indices to cognitive outcomes; (4) the relation of risk factors to neuropathologic indices; and (5) additional study findings. The findings are discussed and contextualized.
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                Author and article information

                Contributors
                mma@augusta.edu
                jinwang@augusta.edu
                qzhang@augusta.edu
                ruwang@augusta.edu
                kdhandapani@augusta.edu
                vadlamudi@uthscsa.edu
                dbrann@augusta.edu
                Journal
                Mol Neurodegener
                Mol Neurodegener
                Molecular Neurodegeneration
                BioMed Central (London )
                1750-1326
                17 January 2017
                17 January 2017
                2017
                : 12
                Affiliations
                [1 ]Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904 USA
                [2 ]Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA 30912 USA
                [3 ]Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 Fifteenth Street, Augusta, GA 30912 USA
                [4 ]Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Medical Drive, San Antonio, TX 78229 USA
                Article
                150
                10.1186/s13024-017-0150-7
                5240251
                28095923
                14aac6a1-6bdb-4cf8-bde9-6373764302d8
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;
                Award ID: 5l101BX001117
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: 5R01NS050730
                Award ID: R01NS088058
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Neurosciences
                nadph oxidase,alzheimer’s disease,stroke,neurodegeneration,oxidative stress,traumatic brain injury,parkinson’s disease,amyotrophic lateral sclerosis,huntington’s disease,multiple sclerosis

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