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Cellular and molecular mechanisms of motor neuron death in amyotrophic lateral sclerosis

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193769 Year: Pages: 190 DOI: 10.3389/978-2-88919-376-9 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-11-19 16:29:12
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Amyotrophic lateral sclerosis (ALS), which was described since 1869 by Jean Martin Charcot, is a devastating neurodegenerative disease characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem and the spinal cord. The cognitive process is not affected and is not merely the result of aging because may occur at young ages. The only known cause of the disease is associated with genetic mutations, mainly in the gene encoding superoxide dismutase 1 (familial ALS), whereas there is no known cause of the sporadic form of ALS (SALS), which comprises >90% of cases. Both ALS types develop similar histopathological and clinical characteristics, and there is no treatment or prevention of the disease. Because effective treatments for ALS, as for other neurodegenerative diseases, can only result from the knowledge of their cellular and molecular pathophysiological mechanisms, research on such mechanisms is essential. Although progress in neurochemical, physiological and clinical investigations in the last decades has identified several mechanisms that seem to be involved in the cell death process, such as glutamate-mediated excitotoxicity, alterations of inhibitory circuits, inflammatory events, axonal transport deficits, oxidative stress, mitochondrial dysfunction and energy failure, the understanding of the origin and temporal progress of the disease is still incomplete and insufficient. Clearly, there is a need of further experimental models and approaches to discern the importance of such mechanisms and to discover the factors that determine the selective death of motor neurons characteristic of ALS, in contrast to other neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Whereas studies in vitro in cell cultures, tissue slices or organotypic preparations can give useful information regarding cellular and molecular mechanisms, the experiments in living animal models obviously reflect more closely the situation in the human disease, provided that the symptoms and their development during time mimics as close as possible those of the human disease. It is necessary to correlate the experimental findings in vitro with those in vivo, as well as those obtained in genetic models with those in non-genetic models, aiming at designing and testing therapeutic strategies based on the results obtained.

Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196913 Year: Pages: 284 DOI: 10.3389/978-2-88919-691-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-04-07 11:22:02
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Mechanisms of brain-immune interactions became a cutting-edge topic in systemic neurosciences over the past years. Acute lesions of the brain parenchyma, particularly, induce a profound and highly complex neuroinflammatory reaction with similar mechanistic properties between differing disease paradigms like ischemic stroke, intracerebral hemorrhage (ICH) and traumatic brain injury (TBI). Resident microglial cells sense tissue damage and initiate inflammation, activation of the endothelial brain-immune interface promotes recruitment of systemic immune cells to the brain and systemic humoral immune mediators (e.g. complements and cytokines) enter the brain through the damaged blood-brain barrier. These cellular and humoral constituents of the neuroinflammatory reaction to brain injury contribute substantially to secondary brain damage and neurodegeneration. Diverse inflammatory cascades such as pro-inflammatory cytokine secretion of invading leukocytes and direct cell-cell-contact cytotoxicity between lymphocytes and neurons have been demonstrated to mediate the inflammatory ‘collateral damage’ in models of acute brain injury. Besides mediating neuronal cell loss and degeneration, secondary inflammatory mechanisms also contribute to functional modulation of neurons and the impact of post-lesional neuroinflammation can even be detected on the behavioral level. The contribution of several specific immune cell subpopulations to the complex orchestration of secondary neuroinflammation has been revealed just recently. However, the differential vulnerability of specific neuronal cell types and the molecular mechanisms of inflammatory neurodegeneration are still elusive. Furthermore, we are only on the verge of characterizing the control of long-term recovery and neuronal plasticity after brain damage by inflammatory pathways. Yet, a more detailed but also comprehensive understanding of the multifaceted interaction of these two supersystems is of direct translational relevance. Immunotherapeutic strategies currently shift to the center of translational research in acute CNS lesion since all clinical trials investigating direct neuroprotective therapies failed. To advance our knowledge on brain-immune communications after brain damage an interdisciplinary approach covered by cellular neuroscience as well as neuroimmunology, brain imaging and behavioral sciences is crucial to thoroughly depict the intricate mechanisms.

Neuroinflammation and Behaviour

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196029 Year: Pages: 181 DOI: 10.3389/978-2-88919-602-9 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2016-08-16 10:34:25
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The brain and immune system are involved in an intricate network of bidirectional communication. This relationship is vital for optimal physiological and psychological development and functioning but can also result in unwanted outcomes. In particular, this interaction plays an important role in cognition, mood and behaviour. Neuroinflammation is known to contribute to neurological and affective disorders including impaired learning and memory, depressive, anxiety and schizoaffective symptoms, as well as pain. The development of these conditions often occurs on the backdrop of pre-existing physical illnesses which give rise to increased activation of the immune system, such as cancer, obesity, infection and autoimmune disorders. Similarly, psychological states can alter regulation of the immune system. This has been most extensively studied in the context of stress and immune function. Understanding the underlying mechanisms that lead to the onset of inflammation-induced neuropathology and stress-induced immune suppression will contribute to the development of novel and effective treatment strategies for both the disease and its neurological side effects. In this research topic we explored the relationship between the immune system and the brain throughout life. We include both original research and review papers from animal, clinical and molecular perspectives.

Cerebral endothelial and glial cells are more than bricks in the Great Wall of the brain: Insights into the way the blood-brain barrier actually works (Celebrating the centenary of Goldman's experiments)

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195725 Year: Pages: 186 DOI: 10.3389/978-2-88919-572-5 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-02-05 17:24:33
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When Ehrlich discovered the first evidence of the blood-brain barrier in 1885, he probably did not perceive the Great Wall that remained hidden from consciousness inside the central nervous system. Ehrlich had observed that acidic vital dyes did not stain the brain if they were injected into the blood stream. A century ago (1913), Goldman showed that the injection of trypan blue in the cerebrospinal fluid stained only the brain, but not the other organs. For almost a century it was thought that the blood-brain barrier (BBB) consisted in a physical barrier, resulting from the restricted permeability of the cerebral endothelial cell layer, as they are joined by tight junctions. However, as scientists are always looking for news in what is already discovered, in the end of the 20th century we had evidences that cerebral endothelial and glial cells express several drug metabolizing enzymes consisting in a second protection system: a metabolic barrier. Furthermore, the drugs and their metabolites must overcome the activity of several multidrug resistance proteins that function as ATP-dependent efflux pumps, consisting in the third line of defence: the active barrier. Therefore, the way the BBB actually works should be better explained. Several endogenous compounds, as well as xenobiotics, may be activated by enzymes of the metabolic barrier, generating reactive oxygen species that could damage neurons. Therefore, endothelial and glial cells possess endogenous protecting compounds and enzymes against oxidants, consisting in an antioxidant barrier. When all these systems fail, glial cells, mainly microglia, secrete cytokines in an attempt to crosstalk with defence cells asking for help, which consists in an immune barrier. In cerebral regions that are devoid of the physical barrier, such as circumventricular organs, the metabolic, active, antioxidant and immune barriers are reinforced. It is important to understand how cells involved in the BBB interact with one another and the dynamic mechanisms of their functions. This Research Topic published in this e-Book considers recent highlights in BBB structure, cell and molecular biology, biotransformation, physiology, pathology, pharmacology, immunology and how these basic knowledges can be applied in drug discovery and clinical researches, rewriting what is already written, and paving the way that goes to the Great Wall in the Frontiers of the Brain in this new century that is just beginning.

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