This book deals with the subject of neuroinflammation and attempts to take the reader on a journey from the bench to the bedside. The microglia and their response to brain injury as well as the importance of the chemokine family are discussed. The relevance of neuroinflammation in experimental models of BSE, scrapie and vCJD as well as Alzheimer's disease, stroke and multiple sclerosis is investigated before proceeding to clinical aspects of neuroinflammation and its involvement in human disease pathophysiology. The book provides an excellent introduction to the field of neuroinflammation and its involvement in human neurodegenerative disease.
The volume includes 75 papers which were presented at the Third International Conference on Intracerebral Hemorrhage, held in Rancho Mirage, California, in March 2010. The topics treated include animal models, pathophysiology of cerebral hemorrhage, experimental treatment for cerebral hemorrhage, cerebral hemorrhage clinical manifestations, prognosis of cerebral hemorrhage, and clinical management. The articles represent the recent advances in hemorrhagic brain injury research presented by highly respected laboratories around the world.
Aneurysmal subarachnoid hemorrhage (SAH) is a stroke subtype that affects, preponderantly, young adults. This condition carries a mortality of approximately 30-50% and a rate of permanent neurological disability of 30%. In addition, a substantial number of patients with an apparent good outcome suffer from residual neurocognitive impairment which, though subtle, prevents them from returning to work and having a normal life. Based on these data, it has been estimated that SAH is responsible for almost a quarter of all the years lost because of stroke. The calcium channel blocker nimodipine remains the only pharmacological treatment for SAH. This drug, however, has limited effectiveness and its use in clinical practice may be limited due to hypotension. Therefore, novel and effective treatments for this condition are desperately needed. The outcome in SAH has been associated with early brain injury, vasospasm, and delayed cerebral ischemia. Mechanistically, these processes are characterized by micro- and macro-vascular dysfunction, microthrombi formation, blood-brain barrier (BBB) dysregulation, brain edema, and neural-cell survival. Soon after SAH, there is a robust inflammatory response characterized by pyrexia, leukocytosis, and upregulation of adhesion molecules and cytokines in the periphery and in the CNS. Observational studies have shown that patients with more severe inflammatory responses experience worse outcomes after SAH. At the molecular level, different proinflammatory intracellular signaling pathways, including mitogen-activated protein-kinase and nuclear factor kappa-β, are activated in cerebral vessels after experimental SAH and their inhibition has been shown to decrease the occurrence of vasospasm. In addition, clinical and preclinical data have linked cytokine upregulation (interleukins [IL]-1B, IL-6 and IL-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1), enhanced expression of adhesion molecules (selectins, integrins, and ICAM), and neutrophil activation to vasospasm of large cerebral arteries, microvascular dysregulation, and cell death. Moreover, immune cells regulate hemostasis and secrete active proteases, including matrix metalloproteinase 9, which promote microthrombosis and induce blood brain barrier dysfunction, respectively. In this context, it has been suggested that an enhanced inflammatory burden might contribute to brain injury in SAH through numerous downstream mechanisms. On the other hand, growing evidence demonstrates that neuroinflammation may influence the proliferation and migration of progenitor cells that participate of synaptic plasticity, neurogenesis, and neurorepair.
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.
Aging is an inevitable part of life, and is becoming a worldwide social, economic and health problem due to the fact that an increasing proportion of individuals in the advanced age category have a higher probability of developing age-related disorders. New therapeutic approaches are still in need to decrease or slow the effects of such diseases in this aging society. Advances in ‘omic technologies such as genomics, transcriptomics, proteomics and metabolomics have significantly advanced our understanding of diseases in multiple medical areas. It is hoped that emerging hits from these analyses might be prioritized for further screening as potential novel drug targets for increasing the human healthspan in line with the lifespan, which will in turn lead to new therapeutic strategies and drug development projects by the pharmaceutical industry. This new book presents a series of reviews describing studies which have resulted in the identification of potential new drug targets for age-related disorders. Much of this information has come from ‘omic comparisons of healthy and disease states or from testing the effects of potential new therapeutic approaches. Each chapter will be presented in the context of specific chronic diseases or different therapeutic strategies, providing important information on disease mechanisms related to the aging process. This book will be of interest to researchers in the areas of aging and chronic disease, as well as clinical scientists, physicians, and major drug companies. With contributors from Australia, Brazil, Canada, France, Germany, India, Iran, Iraq, South Africa, South Korea, Thailand, Ukraine, United Kingdom, United States of America, Uruguay and Vietnam, this is a timely follow up to Guest’s previous book Reviews on New Drug Targets in Age-Related Disorders.
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.
State of the art reviews by experts in the fields of neuroscience, immunology, microbiology/infectious diseases and pharmacology addressing the convergence of the immune system (neuroinflammation) and the loss of neurons (neurodegeneration). Many of the diseases that are discussed in the book are of epidemic proportion, e.g., Alzheimer’s disease, Parkinson’s disease, stroke, viral encephalitides and substance abuse. In addition to discussions of the involvement of neuroinflammation and neurodegeneration in these disorders, scientific reviews are presented on the cells and mediators that participate in defense of and damage to the nervous system. With rare exception, no or inadequate treatment exists for the diseases discussed in this book. An underlying premise of the book is that understanding of their shared pathogenic mechanisms will lead to improved therapies. Given the rapid evolution of the field of Neuroimmune Pharmacology, readers will find this book to be the most timely and authoritative reference on the subject of each of its chapters.
Aging is one of the major risk factors for the onset and progression of various neurodegenerative diseases. Neuroinflammation is a common feature of virtually every central nervous system disease, and is acknowledged as a likely mediator of cognitive impairments. Systemic inflammation levels are augmented with advanced age and neurodegeneration. The influence of age on neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling could magnify the deterioration of the central nervous system microenvironment in disease, and may contribute to enhanced cognitive impairment. This eBook is a collection of highly informative original research articles, providing comprehensive aspect of neuroinflammation and possible therapeutic interventions in rescuing cognitive impairments.
The current progress in molecular medicine allows the identification of a plethora of new and often human-specific drug targets. An early in vivo validation of specific ligands binding to these targets in humans is needed to assess their potential for targeted imaging and radiotherapy. Radiopharmaceuticals are uniquely suitable for such target validation studies. The purpose of the Ernst Schering Research Foundation Workshop 48 was to offer a forum for an open exchange on the state of the art in the early development of such radiopharmaceuticals. Experts from academia, industry and regulatory authorities provided contributions covering the identification of targets, the necessary preclinical studies on the safety of ligands as well as their validation in human clinical trials.
Neuroinflammation, Resolution, and Neuroprotection in the Brain discusses the molecular aspects of neuroinflammation in neurological disorders. The book examines the effect of diet and exercise on neuroinflammatory diseases. Chapters focus on bioactive lipids, cytokines and chemokines, as well as the involvement of neuroinflammation, resolution and neuroprotection in neurotraumatic diseases, neurodegenerative diseases and neuropsychiatric diseases. The comprehensive information in this monograph will help readers understand molecular cross-talk among mediators of phospholipid, sphingolipid and cholesterol metabolism. The book's goal is to jumpstart more studies on molecular mechanisms and the therapeutic aspects of neurological disorders in human subjects. - Discusses the molecular aspects of neuroinflammation, resolution and neuroprotection - Examines the role of diet and exercise on neuroinflammatory diseases - Provides cutting-edge research on signal transduction processes - Explores the treatment of neurological disorders caused by neuroinflammation
