Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders

1st Edition, Volume 71 - September 19, 2014
Imprint: Academic Press
Editor: Thomas P Davis
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 2 8 2 - 7
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 3 3 8 - 1

This new volume of Advances in Pharmacology presents pharmacology of the blood brain barrier, focusing on targeting CNS disorders. With a variety of chapters and the best author… Read more

Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders

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This new volume of Advances in Pharmacology presents pharmacology of the blood brain barrier, focusing on targeting CNS disorders. With a variety of chapters and the best authors in the field, the volume is an essential resource for pharmacologists, immunologists and biochemists alike.

Preface
Chapter One: ABC Transporter Regulation by Signaling at the Blood–Brain Barrier: Relevance to Pharmacology
- Abstract
- 1 Introduction
- 2 ABC Transporters at the Blood–Brain Barrier
- 3 ABC Transporter Regulation
- 4 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Two: P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery
- Abstract
- 1 Introduction
- 2 The BBB/Neurovascular Unit
- 3 Endothelial Cells and the BBB
- 4 Transport Across the Brain Barriers
- 5 P-glycoprotein
- 6 Drug Delivery to the CNS: Strategies Developed to Circumvent Brain Barrier Sites
- 7 Inhibition of Brain Barrier Efflux Transporters
- 8 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Three: Functional Expression of Drug Transporters in Glial Cells: Potential Role on Drug Delivery to the CNS
- Abstract
- 1 Introduction
- 2 Physiological Role of the BBB and Brain Parenchymal Cellular Compartments
- 3 Functional Expression of Drug Transporters in Glial Cells
- 4 Regulation of Drug Transporters in Glial Cells in the Context of Neuropathologies
- 5 Conclusion
- Conflicts of Interest
- Acknowledgments
Chapter Four: Blood–Brain Barrier Na Transporters in Ischemic Stroke
- Abstract
- 1 Introduction
- 2 Ion Transporters and Channels of the BBB
- 3 BBB Na–K–Cl Cotransport and Na/H Exchange in Ischemic Stroke and Cerebral Edema
- 4 Signaling Mechanisms: Roles of AMP Kinase and p38, JNK and ERK MAP Kinases
- 5 Hormonal and Metabolic Factor Effects on BBB Na Transporter Expression and Activities
- 6 Future Directions
- 7 Conclusion
- Conflicts of Interest
- Acknowledgments
Chapter Five: Transcytosis of Macromolecules at the Blood–Brain Barrier
- Abstract
- 1 Introduction
- 2 Mechanisms of Macromolecule Transcytosis
- 3 Endocytosis in Brain Endothelia
- 4 Vesicle Trafficking and Subcellular Localization in Brain Endothelia
- 5 Recycling of Vesicles to Apical or Basolateral Membranes
- 6 Exocytosis in Endothelia
- 7 Targeting Receptor-Mediated Transport for Drug Delivery to Brain
- 8 Conclusion
- Conflict of Interest
Chapter Six: Drug Delivery to the Ischemic Brain
- Abstract
- 1 Introduction
- 2 Pathophysiology of Ischemia
- 3 Drug Delivery to the Hypoxic/Ischemic Brain
- 4 Conclusion
- Conflict of Interest
Chapter Seven: Delivery of Chemotherapeutics Across the Blood–Brain Barrier: Challenges and Advances
- Abstract
- 1 Introduction
- 2 Blood–Brain Barrier Disruption
- 3 Primary CNS Lymphoma
- 4 Chemoprotection Studies
- 5 Advances in Neuroimaging
- 6 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Eight: Delivery of Antihuman African Trypanosomiasis Drugs Across the Blood–Brain and Blood–CSF Barriers
- Abstract
- 1 Introduction
- 2 A Brief History of HAT
- 3 Clinical Presentation of the Disease
- 4 Unique Diagnostic Markers
- 5 Vector
- 6 Diagnosis of HAT
- 7 Treatment of HAT
- 8 Parasite Resistance: Is Combination Therapy the Way Forward?
- 9 BBB Transport of Anti-HAT Drugs
- 10 Latest Research Developments
- 11 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Nine: Delivery of Therapeutic Peptides and Proteins to the CNS
- Abstract
- 1 Introduction
- 2 Obstacles to Delivering Protein and Peptides to the CNS
- 3 Saturable Mechanisms of Peptide and Protein Passage Across the BBB
- 4 Strategies to Enhance the Delivery of Proteins and Peptides to the CNS
- 5 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Ten: Engineering and Pharmacology of Blood–Brain Barrier-Permeable Bispecific Antibodies
- Abstract
- 1 Introduction
- 2 Making the Case for Antibodies as Central Nervous System Therapeutics
- 3 BBB Shuttles for Macromolecules
- 4 Engineering BBB-Permeable Bispecific Antibodies
- 5 Analytical Challenges and Pharmacokinetics/Pharmacodynamics Models
- 6 Conclusion
- Conflict of Interest
Chapter Eleven: Pharmacological Significance of Prostaglandin E₂ and D₂ Transport at the Brain Barriers
- Abstract
- 1 Introduction
- 2 Roles and Kinetics of PGE₂ and PGD₂ in the CNS
- 3 Transporters for PGs and Interspecies Differences
- 4 PGE₂ Efflux Transport System at the BBB
- 5 PGE₂ and PGD₂ Efflux Transport Systems at the BCSFB
- 6 Conclusion
- Conflict of Interest
- Acknowledgments
Chapter Twelve: Steroids and the Blood–Brain Barrier: Therapeutic Implications
- Abstract
- 1 Introduction
- 2 Blood–Brain Barrier
- 3 Steroids and the Brain
- 4 Steroid:BBB Interaction
- 5 Conclusion
- Conflict of Interest
Chapter Thirteen: Combination Approaches to Attenuate Hemorrhagic Transformation After tPA Thrombolytic Therapy in Patients with Poststroke Hyperglycemia/Diabetes
- Abstract
- 1 Introduction
- 2 Increased Hemorrhagic Transformation After tPA Thrombolytic Therapy
- 3 Underlying Mechanisms: Multiple Pathological Pathways
- 4 DM and Hyperglycemia-Mediated Vascular Pathology
- 5 Ischemic Stroke and BBB Disruption
- 6 tPA and Extracellular Proteolysis Dysfunction-Mediated BBB Disruption
- 7 Multiple Pathological Factors and Interactions
- 8 Combination Approaches in Focal Embolic Stroke Model of Hyperglycemia/Diabetic Rats
- 9 Conclusion
- Conflict of Interest
Chapter Fourteen: Aging, the Metabolic Syndrome, and Ischemic Stroke: Redefining the Approach for Studying the Blood–Brain Barrier in a Complex Neurological Disease
- Abstract
- 1 Introduction
- 2 Cell Aging
- 3 Age and the Metabolic Syndrome
- 4 Linking Metabolic Syndrome and Aging
- 5 Conclusion
- Conflict of Interest
Chapter Fifteen: Drug Abuse and the Neurovascular Unit
- Abstract
- 1 Introduction
- 2 Molecular Targets of Common Substances of Abuse
- 3 The Neurovascular Unit
- 4 Transport of Drugs of Abuse into the Brain
- 5 Regulation of the NVU by Drugs of Abuse
- 6 Conclusion
- Conflict of Interest
Index

Thomas P Davis

Professor of Pharmacology, and Program in Physiology and Neuroscience. The University of Arizona College of Medicine. Director of the Laboratory of Blood Brain Barrier Research. Tucson, Arizona. USA.

Dr. Thomas P. Davis has excelled in science, teaching, mentoring and service for over 30 years with consistency and creativity. Dr. Davis’ many accomplishments and work ethic can be credited to his disciplined training by renowned Harvard physiologist, David Bruce Dill, Missouri biochemist and lunar researcher, Charles W. Gehrke, and his University of Arizona College of Medicine mentors, the first Founders Day Lecturer, Henry I. Yamamura, and a College of Medicine founder, John D. Palmer.

Dr. Davis joined the University of Arizona in 1980, after completing two years of rigorous post-doctoral training at Abbott Pharmaceutical Company, as a member of the Therapeutic Drug Delivery (TDx) team. The Abbott TDx program proved highly successful in developing the first non-radioactive, automated, assay platform to monitor therapeutic drug levels in the physician office. Since his arrival at the University of Arizona College of Medicine, Dr. Davis has made outstanding contributions to the field of blood brain barrier (BBB) research by changing how drugs are designed and manufactured by pharmaceutical companies for brain delivery.

Many national and international scientists consider the substantial body of work that he has contributed to the scientific community as ground- breaking. In understanding the role that the blood brain barrier, at the level of the cerebral vasculature, plays in human health and disease, Dr. Davis is regarded as one of the premier investigators in the field. His pioneering studies, showing that drug pharmacokinetics and brain uptake of pain relieving, analgesic agents differ under pathologic conditions, are considered paradigm shifting; thus fundamentally affecting how we approach drug delivery for all CNS disorders, including brain injury, stroke and neurodegeneration. His work on hypoxia, stroke, peripheral pain and drug delivery is credited with the pivotal discovery that macromolecular, structural movement in “tight junction” proteins and drug transporter proteins at the BBB dramatically alters CNS drug delivery, under disease states.

His outstanding record of attracting extramural funding for his research also reflects the quality of Dr. Davis’ work. Since 2000, he has been the Principal Investigator on three continuing National Institutes of Health (NIH) R01 Basic science research grants, the sponsor of seven-funded post-doctoral National research service Awards and six pre-doctoral NIH awards to his students. Each of Dr. Davis’ last seven post-doctoral fellows has been funded by a three year NIH-NRSA grant sponsored by Dr. Davis. This success rate for NIH-NRSA funding may be the highest of record at Arizona; a true testimony to Dr. Davis’ mentoring success. The merit of his highly cited research has been awarded by continuous RO1 and PO1 NIH funding for over 30 consecutive years and publishing over 210 well cited manuscripts leading to a h factor of 50.

His enthusiastic mentorship of more than 50 undergraduate, graduate and medical students, and 25 post-doctoral fellows in his laboratory, since 1982, reflect Dr. Davis’ contribution to the teaching mission of the College of Medicine. Dr. Davis’ success at placing his students in tenure track professor positions, 12 since 2000, demonstrates his dedication and respect as a mentor. He presently coordinates and directs the graduate pharmacology course and sincerely enjoys teaching both graduate and medical students while receiving outstanding teaching evaluations every year.

Affiliations and expertise

Pharmacology, and Program in Physiology and Neuroscience, University of Arizona College of Medicine; Laboratory of Blood Brain Barrier Research, Tucson, Arizona, AZ, USA

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