Nitric Oxide-Mediated Oxidative Damage and the Progressive Demise of Motor Neurons in ALS

    Authors

    D. A. Drechsel; A. G. Estevez; L. Barbeito;J. S. Beckman

    Comments

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    Abbreviated Journal Title

    Neurotox. Res.

    Keywords

    Nitric oxide; Peroxynitrite; Amyotrophic lateral sclerosis; Neurodegeneration; Protein nitration; AMYOTROPHIC-LATERAL-SCLEROSIS; MANGANESE SUPEROXIDE-DISMUTASE; FIBROBLAST-GROWTH-FACTOR; SPINAL-CORD TISSUE; MITOCHONDRIAL; RESPIRATORY-CHAIN; PROTEIN-TYROSINE NITRATION; TRANSGENIC MOUSE MODEL; FACTOR MESSENGER-RNA; FAS DEATH RECEPTOR; ALZHEIMERS-DISEASE; Neurosciences

    Abstract

    Oxidative damage is a common and early feature of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. Dr. Mark Smith and his colleagues have built the case for oxidative stress being a primary progenitor rather than a secondary end-stage epiphenomenon of neurodegeneration. They proposed that reactive oxygen species contribute to the "age-related cascade of neurodegeneration," whereby accumulative oxidative damage with age promotes other characteristic pathological changes in afflicted brain regions, including protein aggregation, metabolic deficiencies, and inflammation. Nitric oxide (NO) likely plays a critical role in this age-related cascade. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through stimulating cyclic GMP synthesis. However, the same physiological concentrations of NO, relevant in cellular signaling, may also initiate and amplify oxidative damage by diffusion-limited reactions with superoxide (O (2) (aEuro cent a') ) to produce peroxynitrite (ONOO (-) ). This is perhaps best illustrated in ALS where physiological levels of NO promote survival of motor neurons, but the same concentrations can stimulate motor neuron apoptosis and glial cell activation under pathological conditions. While these changes represent a complex mechanism involving multiple cell types in the pathogenesis of ALS, they also reveal general processes underlying neurodegeneration.

    Journal Title

    Neurotoxicity Research

    Volume

    22

    Issue/Number

    4

    Publication Date

    1-1-2012

    Document Type

    Review

    Language

    English

    First Page

    251

    Last Page

    264

    WOS Identifier

    WOS:000308966400001

    ISSN

    1029-8428

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