Systemic Inflammatory Regulation of Blood-brain Barrier Inflammation PDF Download

Author: Rebecca Johnson
Publisher:
ISBN:
Category :
Languages : en
Pages : 246

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Book Description
The endothelial cells of the blood-brain barrier are essential for the maintenance of homeostasis in the central nervous system. These cells act as a physical and transport barrier, restricting the movement of systemic immune cells and blood components into the brain. The physical barrier is mediated by the formation of tight and adherens junctions, and the redistribution of these in disease states and systemic inflammation, and the consequent extravasation of immune cells provide valuable targets to reduce neuroinflammation. Multiple Sclerosis is an autoimmune disease in which autoreactive T cells mediate the destruction of the neuronal myelin sheath, leading to a reduction in the speed of neuronal processing, and numerous debilitating symptoms. Blood-brain barrier breakdown is essential to the development of MS, and endothelial cell morphology is vastly different within sites of active lesions and normal appearing white matter. This study attempted to determine the in vitro effect of MS patient serum on the integrity of the endothelial cell barrier and to identify barrier altering components. Individual cytokines which altered the endothelial cell barrier were further analysed to determine their effect on junctional protein expression and the pro-inflammatory secretome. Additionally, the effects of ligands of the toll-like receptor family, a family of innate immune pattern recognition receptors were also analysed, to simulate the effect of systemic bacterial or viral infection at the blood-brain barrier. Interestingly, it was found that the FDA-approved TLR7 ligand imiquimod could increase the endothelial barrier integrity and attenuate the effects of pro-inflammatory stimuli in a TLR7-independent manner. The pathways by which imiquimod was mediating these effects were interrogated, and it was observed that both a cAMP-dependent selective protein kinase A-activator and adenosine A2B receptor agonist could recreate these effects. However, an A2B receptor antagonist did not block the imiquimod-mediated effects. The endothelial cells of the blood-brain barrier are an essential interface between the systemic circulation and the brain. These findings provide novel insights into the effect of pro-inflammatory mediators at this interface and identify potential targets for the modulation of blood-brain barrier permeability and the attenuation of pro-inflammatory insults.

Author: Ruth Lyck
Publisher: Springer
ISBN: 3319455141
Category : Medical
Languages : en
Pages : 288

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Book Description
This PIR volume presents a comprehensive collection of reviews that focus on the role of the blood-brain barrier (BBB) during steady-state and inflamed conditions. Within the central nervous system (CNS) the constantly changing bloodstream is strictly separated from the CNS parenchyma by the BBB. However, viruses, bacteria, parasites and auto-aggressive immune cells can penetrate the barrier and significantly contribute to CNS inflammation. The BBB can actively contribute to neuroinflammation by presentation of chemokines, expression of cell adhesion molecules and alterations of barrier properties. As such, understanding the role of the BBB under healthy and pathological conditions is essential to the development of new drugs to efficiently combat inflammatory diseases of the CNS.

Author: Arthur Liesz
Publisher: Frontiers Media SA
ISBN: 2889196917
Category : Neurosciences. Biological psychiatry. Neuropsychiatry
Languages : en
Pages : 286

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Book Description
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.

Author: Gert Fricker
Publisher: Springer
ISBN: 3662437872
Category : Science
Languages : en
Pages : 169

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Book Description
Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.

Author: Michael Schäfer
Publisher: Springer
ISBN: 3034880391
Category : Medical
Languages : en
Pages : 220

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Book Description
Several new developments in the field of neuroimmunology with focus on the brain-to-immune system communication have been the incentive for this PIR volume. It covers topics such as brain-immune interactions, the impact of stress on the immune response, pain and immunosuppression, the modulation of inflammation and pain by the sympathetic nervous system, consequences of nerve injury for the immune system, neuronal mechanisms of immune cell recruitment, and the modulation of the immune response by corticotropin-releasing hormone or adenosine. The authors are a unique group of scientists who are all interested in brain-to-immune interactions; however, each from a different perspective. The volume will serve both neurobiologists and immunologists to understand the influence of the central nervous system on peripheral inflammation. Many aspects of this book will also be stimulating for researchers in the pain field.

Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 324

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Book Description
Currently, there is a growing body of research characterizing the blood-brain barrier (BBB) under normal physiological conditions; however, little is known about BBB regulation under pathophysiological conditions, such as inflammatory pain. This dissertation elucidates peripheral inflammatory pain effects on the BBB both functionally in terms of permeability and structurally via tight junction (TJ) protein expression and regulation. Inflammation was produced by subcutaneous injection of formalin, lambda-carrageenan, or complete Freund's adjuvant (CFA) into the right hind paw of rats. In situ perfusion and Western blot analyses were performed to assess BBB integrity after inflammatory insult. In situ brain perfusion determined that peripheral inflammation significantly increased the uptake of a membrane impermeant marker, sucrose into the cerebral hemispheres in all inflammatory models. Subsequently, a 0-168h time course study of lambda-carrageenan-induced inflammatory pain elicited a biphasic increase in BBB permeability of sucrose with the first phase occurring from 1-6h and the second phase occuring at 48h. Lambda-carrageenan-induced inflammatory pain also increased brain uptake of a commonly used analgesic, codeine at the same time-points. This is the first known observation that peripheral inflammation results in greater analgesic drug uptake to the brain. This uptake also correlated with its antinociceptive profile over a 168h time course. This suggests the presence of inflammatory pain may be an important consideration in therapeutic drug dosing, potential adverse effects and/or neurotoxicity. Western blot analyses showed altered TJ protein expression during peripheral inflammation. Occludin significantly decreased in the lambda-carrageenan- and CFA-treated groups. ZO-1 expression was significantly increased in all pain models. Claudin-1 protein expression was present at the BBB and remained unchanged during inflammation. Actin expression was significantly increased in the lambda-carrageenan- and CFA-treated groups. Over a 72h time period with lambda-carrageenan-induced inflammatory pain, altered TJ protein expression of occludin and ZO-1 correlated with permeability changes in BBB function. This is the first report of peripheral inflammation inducing alterations in TJs and increasing permeability of the BBB. This dissertation demonstrates that changes in the structure of TJs leading to alterations in the BBB may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.

Author: Daniel Laskowitz
Publisher: CRC Press
ISBN: 1498766579
Category : Medical
Languages : en
Pages : 388

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Book Description
Traumatic brain injury (TBI) remains a significant source of death and permanent disability, contributing to nearly one-third of all injury related deaths in the United States and exacting a profound personal and economic toll. Despite the increased resources that have recently been brought to bear to improve our understanding of TBI, the developme

Author:
Publisher: Elsevier
ISBN: 0444535454
Category : Medical
Languages : en
Pages : 362

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Book Description
It is now well recognized that the brain, and especially the hypothalamus, plays an important role in the regulation of immune reactions and inflammation. This book aims to review our current state of knowledge of this important field. Key historical findings are presented, and the reciprocal interactions between the brain and the immune system are examined. Particular emphasis is placed on inflammation, a critical host defense reaction that serves as an effector response for both the adaptive and innate immune systems.Mechanisms implicated in brain defense, as well as in more general host defense, are discussed. The regulatory influences of the brain on inflammatory responses are included with particular reference to the role of the hypothalamus, which is also the main director the hormonal regulation of immune/inflammatory. Gender-related differences in immune responsiveness, circadian modulator of immune responses, and evidence that behavioral conditioning (e.g. reward) of immune responses is possible are used as examples to reinforce the notion that the neuroendocrine system exerts a fundamental and complex regulatory influence on the immune system. - Presents timely issues such as immunological aspects of the blood-brain-barrier and the role of inflammatory mediators in the evolution of strokes and degenerative diseases - Includes analysis of the role of the brain in the adaptive responses to disease - Evaluates the argument that further knowledge of the influence of the brain on the immune system will provide new insights to the pathophysiology infectious and autoimmune diseases

Author: Ulrich Dirnagl
Publisher: Springer Science & Business Media
ISBN: 3662054264
Category : Medical
Languages : en
Pages : 248

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Book Description
The successful treatment of acute stroke remains one of the major challenges in clinical medicine. Over the last decades, the understanding of stroke pathophysiology has greatly improved, while the therapeutic options in stroke therapy remain very limited. Today, hyperacute mechanisms of damage, such as excitotoxicity, can be discriminated from delayed ones, such as inflammation and apoptosis. Targeting of inflammation has already been successfully applied in various stroke models, but translation into a clinically efficacious strategy has not been achieved so far. In this book, leading experts in basic cerebrovascular research as well as stroke treatment review the current evidence for and against an important role for inflammation in stroke, and explore the potential of treating or modulating inflammation in stroke therapy.

Author: Hubert Vaudry
Publisher: Springer Science & Business Media
ISBN: 9781402073069
Category : Medical
Languages : en
Pages : 432

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Book Description
Pituitary Adenylate Cyclase-Activating Polypeptide is the first volume to be written on the neuropeptide PACAP. It covers all domains of PACAP from molecular and cellular aspects to physiological activities and promises for new therapeutic strategies. Pituitary Adenylate Cyclase-Activating Polypeptide is the twentieth volume published in the Endocrine Updates book series under the Series Editorship of Shlomo Melmed, MD.