This e-book will review special features of the cerebral circulation and how they contribute to the physiology of the brain. It describes structural and functional properties of the cerebral circulation that are unique to the brain, an organ with high metabolic demands and the need for tight water and ion homeostasis. Autoregulation is pronounced in the brain, with myogenic, metabolic and neurogenic mechanisms contributing to maintain relatively constant blood flow during both increases and decreases in pressure. In addition, unlike peripheral organs where the majority of vascular resistance resides in small arteries and arterioles, large extracranial and intracranial arteries contribute significantly to vascular resistance in the brain. The prominent role of large arteries in cerebrovascular resistance helps maintain blood flow and protect downstream vessels during changes in perfusion pressure. The cerebral endothelium is also unique in that its barrier properties are in some way more like epithelium than endothelium in the periphery. The cerebral endothelium, known as the blood-brain barrier, has specialized tight junctions that do not allow ions to pass freely and has very low hydraulic conductivity and transcellular transport. This special configuration modifies Starling's forces in the brain microcirculation such that ions retained in the vascular lumen oppose water movement due to hydrostatic pressure. Tight water regulation is necessary in the brain because it has limited capacity for expansion within the skull. Increased intracranial pressure due to vasogenic edema can cause severe neurologic complications and death.

This volume focuses on experimental research with applicable models to study physiology, biochemistry, and molecular biology of the blood-brain barrier (BBB). This book is organized into six parts: Part One is an overview of the physiology of BBB; Part Two explores in vitro cell models to study the BBB; Part Three discusses techniques in vivo and ex vivo models to evaluate BBB in Drosophila melanogaster, Zebrafish, and rodents; Part Four looks at permeability, influx, efflux transportation, and drug delivery through the BBB; Part Five talks about various invasive and non-invasive imaging techniques to study BBB; and Part Six describes how molecular biomarkers are used to look at the integrity or dysfunction of the BBB. In Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and thorough, Blood-Brain Barrier is a valuable resource to aid both novice and experienced investigators with performing experiments using new and classic translational approaches.

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

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.

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.

The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.

Focused on central nervous system (CNS) drug discovery efforts,this book educates drug researchers about the blood-brain barrier(BBB) so they can affect important improvements in one of the mostsignificant – and most challenging – areas of drugdiscovery. • Written by world experts to provide practicalsolutions to increase brain penetration or minimize CNSside-effects • Reviews state-of-the-art in silico, in vitro, and invivo tools to assess brain penetration and advanced CNS drugdelivery strategies • Covers BBB physiology, medicinal chemistry designprinciples, free drug hypothesis for the BBB, and transportmechanisms including passive diffusion, uptake/efflux transporters,and receptor-mediated processes • Highlights the advances in modelling BBBpharmacokinetics and dynamics relationships (PK/PD) andphysiologically-based pharmacokinetics (PBPK) • Discusses case studies of successful CNS and non-CNSdrugs, lessons learned and paths to the market

The blood-brain barrier is still not completely understood and therefore the subject of fascinating study. How are endogenous substances transported through the blood-brain barrier? What are the known therapeutic and toxic agents? How are they transported across cerebral microvessels? The discussion of these and other questions with far-reaching consequences for all neuroscientists can be found in this volume. This authoritative and up-to-date review of the blood-brain barrier gives a proper understanding of the topic. The experimental principles, the results of very recent research, as well as the implications that experimental research has for clinical treatment are thoroughly covered. Information is given on: - new findings based on classical physiological and pharmacological techniques, - results obtained from brain capillaries in vitro and in culture, - results obtained from the new scanning techniques (PET and MRI), - the immunology of the blood-brain barrier, - trace metal transport, - the pathological breakdown of the barrier and - the modification of drugs to increase their entry into the brain. Here is a source of information that is invaluable to specialists concerned with basic research in the neurosciences, with the design of neuropharmacological agents, with the radiological diagnosis of cerebral pathology or with the treatment of cerebral lesions!

This is the first handbook to integrate developmental and cellular aspects combining the different structural and functional features involved in the regulation of brain perfusion and neuronal function. It highlights pharmacological and biomedical applications with sections on drug delivery and disease-related states as well as explaining in detail the role of astrocytes, shown to be an essential link between neurons and cerebral blood vessels. In addition the book studies how the structural elements interact in response to the dynamics of neuronal activities, necessitating adaptive mechanism of the interface. A significant part of the book describes new approaches to how the barrier can be surmised for drug delivery and how it can be mimicked by artificial in vitro systems for drug testing. Finally, the involvement of the barrier in brain diseases is considered, focusing on inflammatory and neurodegenerative disorders of the brain. Covering basic knowledge as well as specific information dealing with very recent progress in blood-brain interface research, this book is of interest to neurobiologists, neurologists, biochemists, and pharmacologists.

As traced by Uichael Bradbury in his recently published monograph, The Concept of a BZood-Brain Barrier, the idea of a scientific challenge is just about as old as the twentieth century. Curiously, it remains undefined. Is it a structure or structures as some use the term, or is it a reciprocal per meability, a force-flow relationship, as do others, or is it a group of processes, some more specialized than others? Depend ing upon the observer, the method, and what is observed, it seems to be each of these or all. This Symposium takes as its focus of interest the micro vasculature of the brain and includes considerations of blood flow, the properties of vessel walls and the control of flow and permeability. In addition perturbations that change the characteristics of the flow of materials are given attention. By changing the usual focus of interest, the organizers, Drs. Suddith and Eisenberg, have given a fresh outlook to the subject and now, by publication of the Proceedings, have arranged for wide availability of these interesting papers. Keasley Welch v PREFACE A symposium on the cerebral microvasculature and its function in the blood-brain barrier was held at The University of Texas Medical Branch, Galveston, in the summer of 1979. Investigators from the United States and Europe met to discuss their recent work.