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      Redox Signaling in Neurotransmission and Cognition During Aging

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          Abstract

          Significance: Oxidative stress increases in the brain with aging and neurodegenerative diseases. Previous work emphasized irreversible oxidative damage in relation to cognitive impairment. This research has evolved to consider a continuum of alterations, from redox signaling to oxidative damage, which provides a basis for understanding the onset and progression of cognitive impairment. This review provides an update on research linking redox signaling to altered function of neural circuits involved in information processing and memory.

          Recent Advances: Starting in middle age, redox signaling triggers changes in nervous system physiology described as senescent physiology. Hippocampal senescent physiology involves decreased cell excitability, altered synaptic plasticity, and decreased synaptic transmission. Recent studies indicate N-methyl- d-aspartate and ryanodine receptors and Ca 2+ signaling molecules as molecular substrates of redox-mediated senescent physiology.

          Critical Issues: We review redox homeostasis mechanisms and consider the chemical character of reactive oxygen and nitrogen species and their role in regulating different transmitter systems. In this regard, senescent physiology may represent the co-opting of pathways normally responsible for feedback regulation of synaptic transmission. Furthermore, differences across transmitter systems may underlie differential vulnerability of brain regions and neuronal circuits to aging and disease.

          Future Directions: It will be important to identify the intrinsic mechanisms for the shift in oxidative/reductive processes. Intrinsic mechanism will depend on the transmitter system, oxidative stressors, and expression/activity of antioxidant enzymes. In addition, it will be important to identify how intrinsic processes interact with other aging factors, including changes in inflammatory or hormonal signals. Antioxid. Redox Signal. 28, 1724–1745.

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          Most cited references261

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          Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

          Redox state is a term used widely in the research field of free radicals and oxidative stress. Unfortunately, it is used as a general term referring to relative changes that are not well defined or quantitated. In this review we provide a definition for the redox environment of biological fluids, cell organelles, cells, or tissue. We illustrate how the reduction potential of various redox couples can be estimated with the Nernst equation and show how pH and the concentrations of the species comprising different redox couples influence the reduction potential. We discuss how the redox state of the glutathione disulfide-glutathione couple (GSSG/2GSH) can serve as an important indicator of redox environment. There are many redox couples in a cell that work together to maintain the redox environment; the GSSG/2GSH couple is the most abundant redox couple in a cell. Changes of the half-cell reduction potential (E(hc)) of the GSSG/2GSH couple appear to correlate with the biological status of the cell: proliferation E(hc) approximately -240 mV; differentiation E(hc) approximately -200 mV; or apoptosis E(hc) approximately -170 mV. These estimates can be used to more fully understand the redox biochemistry that results from oxidative stress. These are the first steps toward a new quantitative biology, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.
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            NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.

            NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.
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              Inflammatory markers in population studies of aging.

              To review findings from major epidemiologic studies regarding risk factors for and consequences of elevated markers of inflammation in older adults. Most large, current epidemiologic studies of older adults have measured serum interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) and some studies also include more extensive batteries of measures including soluble receptors. There are few defined risk factors for the modest elevations in inflammatory markers seen with aging. These include visceral adiposity, lower sex steroid hormones, smoking, depression and periodontal disease. Of the markers assessed, IL-6 is most robustly associated with incident disease, disability and mortality. Though correlated with age, the etiology of elevated inflammatory markers remains incompletely defined. Inflammation, especially IL-6 may be a common cause of multiple age-related diseases or a final common pathway by which disease leads to disability and adverse outcomes in older adults. Future research targeting inflammation should examine these pathways. Copyright © 2011. Published by Elsevier B.V.
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                Author and article information

                Journal
                Antioxid Redox Signal
                Antioxid. Redox Signal
                ars
                Antioxidants & Redox Signaling
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1523-0864
                1557-7716
                20 June 2018
                20 June 2018
                20 June 2018
                : 28
                : 18
                : 1724-1745
                Affiliations
                [ 1 ]Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida.
                [ 2 ]Genetics and Genomics Program, Genetics Institute, University of Florida , Gainesville, Florida.
                Author notes
                Address correspondence to: Dr. Ashok Kumar, Department of Neuroscience, McKnight Brain Institute, University of Florida PO Box 100244, Gainesville, FL 32610-0244, E-mail: kash@ 123456ufl.edu
                Dr. Thomas C. Foster, Department of Neuroscience, McKnight Brain Institute, University of Florida PO Box 100244, Gainesville, FL 32610-0244, E-mail: foster1@ 123456ufl.edu
                Article
                10.1089/ars.2017.7111
                10.1089/ars.2017.7111
                5962336
                28467718
                20034efd-2075-454f-9c11-00ae269ee1d1
                © Ashok Kumar, et al., 2018; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are cited.

                History
                : 07 April 2017
                : 01 May 2017
                Page count
                Figures: 8, References: 305, Pages: 22
                Categories
                Forum Review Articles

                aging,ca2+ signaling,cognition,nmda receptor,oxidative stress,redox regulation

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