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      Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

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          Abstract

          Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases.

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          Most cited references182

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          HMG-1 as a late mediator of endotoxin lethality in mice.

          Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
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            Control of microglial neurotoxicity by the fractalkine receptor.

            Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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              Is Open Access

              Neuroinflammation: friend and foe for ischemic stroke

              Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2020
                1 August 2020
                : 2020
                : 8363245
                Affiliations
                1Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
                2Department of Medical Science, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy
                3Toscana Life Sciences, 53100 Siena, Italy
                4Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
                5Department of Biomedical and Dental Sciences and Morphofunctional Imaging, AOU Policlinico Universitario “G. Martino”, 98125 Messina, Italy
                6Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
                7Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47900 Rimini, Italy
                Author notes

                Academic Editor: Andrey V. Kozlov

                Author information
                https://orcid.org/0000-0002-8415-3711
                https://orcid.org/0000-0001-6627-7078
                https://orcid.org/0000-0002-9564-214X
                https://orcid.org/0000-0001-9999-2780
                https://orcid.org/0000-0002-6827-7327
                https://orcid.org/0000-0002-3980-0043
                https://orcid.org/0000-0002-5481-7572
                https://orcid.org/0000-0001-5650-760X
                https://orcid.org/0000-0003-0349-7772
                https://orcid.org/0000-0001-6494-5968
                https://orcid.org/0000-0001-7857-4512
                Article
                10.1155/2020/8363245
                7422410
                32832006
                b095b4c5-15f2-43a1-84da-b71c367057d9
                Copyright © 2020 Patrizia Hrelia et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 May 2020
                : 15 July 2020
                Funding
                Funded by: Ministero dell'Istruzione, dell'Università e della Ricerca
                Award ID: 20152HKF3Z
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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