New Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration
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New Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration explores traumatic brain injury (TBI), a major cause of death and disability throughout the world. The delayed nature of the secondary injury phase suggests that there is a therapeutic window for pharmacological interventions or other approaches to prevent progressive tissue damage and improve functional outcomes. It is now apparent that therapeutic interventions should entail both protective and repair/regeneration strategies depending on the phase of brain injury.
This book describes emerging experimental strategies for the treatment of TBI, including new anti-inflammatory or anti-apoptotic therapeutics that limit brain damage, and novel or repurposed drugs that enhance repair or regeneration of the brain after injury.
- Comprehensive overview of basic approaches and translational development of new therapies for TBI
- Edited by a prominent TBI researcher that includes contributions by leading global researchers in the field
- Presents a great resource for researchers and practitioners to learn more about the many evolving preclinical studies and clinical trials currently underway, and the challenges of bringing translational studies in TBI to the clinic
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New Therapeutics for Traumatic Brain Injury - Kim Heidenreich
New Therapeutics for Traumatic Brain Injury
Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration
Editor
Kim A. Heidenreich
University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
Table of Contents
Cover image
Title page
Copyright
List of Contributors
Foreword
Preface
Introduction
Part I. Interventional Therapies for TBI Previously or Currently in Phase 3 Clinical Trials
Chapter 1. Why Did the Phase III Clinical Trials for Progesterone in TBI Fail? An Analysis of Three Potentially Critical Factors
Introduction: Progesterone Treatment Showed Promise in Preclinical Research
The Phase II Trials
The Phase III Trials
Factors Contributing to the Trial Failures
Further Issues in the Trial Failures: Dosing, Duration of Treatment, Vehicle Effects
Chapter 2. Hypothermia for Traumatic Brain Injury: Current Evidence and Future Directions
Introduction
Mechanisms of Protection and Potential Side Effects
Management Strategies
Efficacy Studies
Conclusions and Future Directions
Chapter 3. The Future of TBI: Hyperbaric Oxygen as a Primary Therapeutic Approach
Introduction
A Brief History of HBOT
What Is Traumatic Brain Injury?
Symptoms of Traumatic Brain Injury
The Military and Traumatic Brain Injury
Sports and the National Football League
The Science Behind HBOT for Traumatic Brain Injury
Clinical Trials of HBOT for Traumatic Brain Injury
Potential Side Effects and Current Use
Conclusions
Part II. Repurposing FDA Approved Drugs for TBI Treatment
Chapter 4. Erythropoietin and Its Derivatives: Mechanisms of Neuroprotection and Challenges in Clinical Translation
Neurodegeneration and Neurogenesis After Traumatic Brain Injury
Erythropoietin as an Endogenous Neuroprotective Molecule
Derivatives of Erythropoietin
Preclinical Studies of Erythropoietin in Stroke
Erythropoietin in Other Animal Models of Brain Disease
Preclinical Studies of Erythropoietin in Traumatic Brain Injury
Erythropoietin Promotes Angiogenesis
Human Trials With Erythropoietin During the Acute Phase of Ischemic Stroke and Traumatic Brain Injury
Conclusions
Author Contributions
List of Abbreviations
Chapter 5. Atorvastatin in the Treatment of Traumatic Brain Injury
Introduction
Pharmacodynamics
Pharmacokinetics and Adverse Effects
Clinical Investigations
Conclusion
Chapter 6. The Application of Glibenclamide in Traumatic Brain Injury
Sulfonylurea Receptor 1 and Its Role in Central Nervous System Injury
Glibenclamide—A Potent Inhibitor of Sulfonylurea Receptor 1
Sulfonylurea Receptor 1 and Glibenclamide in the Setting of Traumatic Brain Injury
Summary
Chapter 7. Perispinal Etanercept for Traumatic Brain Injury
Background
Perispinal Etanercept for Treatment of Traumatic Brain Injury
Part III. Interventional Drugs for TBI in Phase 1–2 Clinical Trials
Chapter 8. Nitric Oxide Synthase Inhibitors in Traumatic Brain Injury
Introduction
Changes of NO Metabolism in the Brain After TBI
NOS Inhibitors in Experimental TBI
Tetrahydrobiopterin Antagonists as NOS Inhibitors
VAS203 in the Treatment of TBI
Chapter 9. Management of Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury
Introduction
Nomenclature
Incidence
Mechanism: Theories
Neurological and Functional Outcomes
Systemic Consequences
Psychiatric Consequences
Management of PSH
Ongoing Clinical Trial
A Final Consideration
Summary
Part IV. Interventional Drugs for TBI in Preclinical Development
Chapter 10. The Use of Estrogen for the Treatment of Traumatic Brain Injury
Background
The Golden Hour
Mechanisms of Estrogen Action
The Neuroprotective Effects of Estrogens
Neuronal Stretch Assay
Multiple Therapies from One Drug
Formulating a Drug
Estrogen and Traumatic Brain Injury
Results
Summary
Chapter 11. Voltage-Gated Calcium Channel Blockers for the Treatment of Traumatic Brain Injury
Traumatic Brain Injury
Traumatic Brain Injury and [Ca²+]i
Voltage-Gated Calcium Channels
Neuroprotective Effects of Voltage-Gated Calcium Channel Blockers
Chronic Pain
Conclusion
Chapter 12. 5-Lipoxygenase-Activating Protein Inhibitors: Promising Drugs for Treating Acute and Chronic Neuroinflammation Following Brain Injury
Leukotrienes
Approved Antileukotriene Drugs
The Discovery of 5-Lipoxygenase-Activating Protein and the Development of 5-Lipoxygenase-Activating Protein Inhibitors
The Potential Use of 5-Lipoxygenase-Activating Protein Inhibitors in Acute Brain Injury
The Potential Use of 5-Lipoxygenase-Activating Protein Inhibitors in Prolonged Neuroinflammation Following Mild Traumatic Brain Injury
Conclusions
Chapter 13. Carbonyl Scavenging as an Antioxidant Neuroprotective Strategy for Acute Traumatic Brain Injury
Introduction
Basics of Free Radical-Induced LP
Increase in LP-Derived Aldehydes 4-HNE and Acrolein in Acute Traumatic Spinal Cord or Brain Injury and Association With Mitochondrial Dysfunction
Comparative Effects of 4-HNE and Acrolein on Brain and Spinal Cord Mitochondria
Carbonyl Scavenging as an Antioxidant Neuroprotective Strategy
Neuroprotective Effects of Phenelzine in Experimental TBI
Ongoing Studies on Phenelzine Carbonyl Scavenging-Mediated Neuroprotection
Chapter 14. TrkB Receptor Agonist 7,8-Dihydroxyflavone and Its Therapeutic Potential for Traumatic Brain Injury
Introduction
Neurotrophins and Tropomyosin Receptor Kinase B Receptor
TrkB Signaling Pathways and Its Function
The Molecule 7,8-Dihydroxyflavone
Therapeutic Potential of 7,8-Dihydroxyflavone for Neurological Diseases
Current Experimental Findings of 7,8-Dihydroxyflavone in the Treatment of Traumatic Brain Injury
Conclusion and Perspectives
Chapter 15. Ceftriaxone Treatment of TBI
Traumatic Brain Injury and Glutamate Excitotoxicity
Glutamate Physiology and Homeostasis
Posttraumatic Changes in the Brain: GLT-1, PTE, and Beyond
Ceftriaxone Is a Safe, Widely Used Antibiotic
Ceftriaxone Increases GLT-1 Expression and Mitigates Post-TBI Consequences
Ceftriaxone Decreases Oxidative Stress Independently of Glutamate Transport
Ceftriaxone Alternatives
Conclusion
Part V. Drugs for TBI Rehabilitation
Chapter 16. Memantine: A Safe and Tolerable NMDA Antagonist with Potential Benefits in Traumatic Brain Injury
Introduction
NMDA Receptors: Crucial for Memory, But Potentially Excitotoxic
NMDA Antagonists Vis-à-Vis Excitotoxicity in TBI and Ischemia
Memantine: An NMDA Antagonist Without the Undesirable Side Effects
Memantine: Formulations, Dosages, Contraindications, and Side Effects
The Potential Neuroprotective Effects of Memantine
Memantine in TBI: Preclinical Studies
Memantine in Human TBI: Empirical Studies and Considerations
Conclusions and Future Directions
Chapter 17. Interventional Drugs for TBI Rehabilitation of Cognitive Impairment: The Cholinesterase Inhibitor Rivastigmine
Introduction
Cholinesterase Inhibitors in TBI
Rivastigmine in TBI
Conclusions: The Next Step(s)
Chapter 18. Docosahexaenoic Acid and Omega 3 Fatty Acids
Docosahexaenoic Acid and Omega 3 Fatty Acids
Omega 6 and Omega 3 Polyunsaturated Fatty Acids: A Brief Overview
Brain DHA Content is Highly Conserved
Role of Omega-3 PUFAs in Normal Brain Development and Function
Role of DHA in Normal Neural Membrane Composition and Function
Preexisting DHA Deficiency Worsens Outcomes After Experimental TBI
Possible Role of an Acquired DHA Deficiency After TBI
Effects of n-3 PUFAs on Neuroinflammation
Role of n-3 PUFAs in Oxidative Injury After TBI
Omega 3 PUFAs in Experimental TBI
Omega 3 PUFAs in Clinical TBI
Unanswered Questions and Future Directions
Chapter 19. Treatment of Mood Disorders Following Traumatic Brain Injury
Introduction
Depressive Disorders
Manic and Mixed Mood Disorders
Index
Copyright
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ISBN: 978-0-12-802686-1
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Cover image appears courtesy of the USC Laboratory of Neuro Imaging and the Athinoula A. Martinos Center for Biomedical Imaging, Consortium of the Human Connectome Project, www.humanconnectomeproject.org
List of Contributors
M.J. Bell, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
R.F. Berman, University of California, Davis, Davis, CA, United States
J.D. Bernstock, National Institutes of Health (NIH), Bethesda, MD, United States
T. Bogoslovsky, Uniformed Services University of the Health Sciences (USUHS), Rockville, MD, United States
O. Brawman-Mintzer
Ralph H. Johnson VA Medical Center, Charleston, SC, United States
Medical University of South Carolina, Charleston, SC, United States
J.E. Cebak, University of Kentucky College of Medicine, Lexington, KY, United States
I.H. Chaudry, University of Alabama at Birmingham, Birmingham, AL, United States
C.E. Corser-Jensen, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
R. Diaz-Arrastia, Uniformed Services University of the Health Sciences (USUHS), Rockville, MD, United States
H.M. Eisenberg, University of Maryland School of Medicine, Baltimore, MD, United States
L.A. Fox, Jupiter Medical Center, Jupiter, FL, United States
S.P. Gopinath, Baylor College of Medicine, Houston, TX, United States
G.G. Gurkoff, University of California, Davis, Davis, CA, United States
E.D. Hall, University of Kentucky College of Medicine, Lexington, KY, United States
M.Q. Hameed, Harvard Medical School, Boston, MA, United States
K.A. Heidenreich, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
M.A. Hernandez-Tejada
Ralph H. Johnson VA Medical Center, Charleston, SC, United States
Medical University of South Carolina, Charleston, SC, United States
D.S. Hersh, University of Maryland School of Medicine, Baltimore, MD, United States
R.L. Hill, University of Kentucky College of Medicine, Lexington, KY, United States
R.B. Howard, Emory University (Former), Atlanta, GA, United States
W.J. Hubbard, University of Alabama at Birmingham, Birmingham, AL, United States
R.E. Jorge
Michael E. DeBakey VA Medical Center, Houston, TX, United States
Baylor College of Medicine, Houston, TX, United States
M.A. Keiski, University of Alabama at Birmingham, Birmingham, AL, United States
K. Kenney, Uniformed Services University of the Health Sciences (USUHS), Rockville, MD, United States
N. Kim, Institute of Neurological Recovery (INR), Los Angeles, CA, United States
R. Kinssies, Institute of Neurological Recovery (INR PLLC), Boca Raton, FL, United States
J.R. Kulbe, University of Kentucky College of Medicine, Lexington, KY, United States
T.C. Leath, Vanderbilt University Medical Center, Nashville, TN, United States
H.L. Lin
Michael E. DeBakey VA Medical Center, Houston, TX, United States
Baylor College of Medicine, Houston, TX, United States
B.G. Lyeth, University of California, Davis, Davis, CA, United States
B. Miskin, Jupiter Medical Center, Jupiter, FL, United States
C. Moore, Uniformed Services University of the Health Sciences (USUHS), Rockville, MD, United States
H. Mtaweh, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada
M.B. Patel
Vanderbilt University Medical Center, Nashville, TN, United States
US Department of Veterans Affairs, Nashville, TN, United States
C.S. Robertson, Baylor College of Medicine, Houston, TX, United States
H. Rodriguez-Romanacce
Institute of Neurological Recovery (INR), Los Angeles, CA, United States
Institute of Neurological Recovery (INR PLLC), Boca Raton, FL, United States
J. Romeika, Virginia Commonwealth University, Richmond, VA, United States
A. Rotenberg, Harvard Medical School, Boston, MA, United States
I. Sayeed, Emory University, Atlanta, GA, United States
R. Schinzel, Vasopharm GmbH, Würzburg, Germany
M.E. Schober, University of Utah School of Medicine, Salt Lake City, UT, United States
A.N. Sen, Baylor College of Medicine, Houston, TX, United States
K. Shahlaie, University of California, Davis, Davis, CA, United States
J.M. Simard, University of Maryland School of Medicine, Baltimore, MD, United States
D. Simon, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
I.N. Singh, University of Kentucky College of Medicine, Lexington, KY, United States
D.G. Stein, Emory University, Atlanta, GA, United States
D. Sun, Virginia Commonwealth University, Richmond, VA, United States
F. Tegtmeier, Vasopharm GmbH, Würzburg, Germany
E. Tobinick
Institute of Neurological Recovery (INR), Los Angeles, CA, United States
Institute of Neurological Recovery (INR PLLC), Boca Raton, FL, United States
J.A. Wang, University of Kentucky College of Medicine, Lexington, KY, United States
L.D. Wilson
Vanderbilt University Medical Center, Nashville, TN, United States
University of Tulsa, Tulsa, OK, United States
M. Wurzelmann, Virginia Commonwealth University, Richmond, VA, United States
Foreword
Thirty years ago, optimism about developing new therapies for traumatic brain injury (TBI) abounded. Exciting advances in molecular biology, transgenic mice, and injury models made new therapeutics seem within reach. What happened? The answer is found in this book—New Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration. The editor carefully selected many of the most promising therapies for inclusion in the book and invited leaders in the field to review the scientific rationale for testing them, the state of the research, and their insights and perspectives on where we go next.
Each chapter stands on its own by comprehensively describing how these candidate therapies alter mechanisms of injury and repair, and the research designs, doses, and models that were used to evaluate their efficacy or effectiveness. The chapters about progesterone and hypothermia are especially provocative because the story is more complete—these candidate therapies made it all the way to large, multicenter clinical trials. Even when studies fail to demonstrate superior effectiveness over controls, we owe it to patients and the public to learn as much as we can from the research.
It is the collection of experiences, though, that are particularly valuable for assessing the state of the science of therapy development for TBI. While I am tempted to add my views, instead, I would encourage you to read this book, step back, and ask yourself, where do we go from here? Giving up is not an option; nor is repeating the past. This book can help us find a path forward.
Ramona Hicks
Preface
When approached by Elsevier to compile a book about current research aimed at finding a treatment for traumatic brain injury, I immediately agreed and embraced the idea. I have spent my scientific research career studying the brain. As a neuroscientist, I have investigated how the brain controls our body’s function, perception, thinking, behavior, and emotions. All of these activities are mediated by a complex network of connections and interactions between the 100 billion neurons and at least 10 times that number of glial cells in the human brain. It is not surprising that damage to the brain, even mild injury, can lead to devastating neurologic consequences that may last a lifetime.
While investigating the cellular mechanisms of neurodegenerative diseases, I was asked by a colleague, Dr. Robert Murphy to collaborate on a graduate student’s research project. The student was Santiago Farias, who came to Colorado after his home and research space were destroyed by hurricane Katrina. Santiago wanted to learn and apply mass spectrometry (MS) methods to the brain. With my background in neuroscience and experience in culturing primary neurons, and Bob’s expertise as a lipid biochemist who has spent his career studying leukotrienes, we designed a research project to determine if the brain could synthesize leukotrienes. At the time, I had a rudimentary knowledge of eicosanoids, a large family of lipid mediators that are derived from arachidonic acid (AA) released from the cell membrane by phospholipases. I remembered that leukotrienes are a class of eicosanoids produced in leuko
cytes and have a common conjugated triene
in their structure. I also knew that leukotrienes evoke primarily proinflammatory responses by activating G-coupled receptors present on virtually all cells. Moreover, I recalled that they play a major role in asthma, a chronic inflammatory disease of the lungs. At the time, I had no idea that our research project would open the world of neuroinflammation to me and lead to a potential therapy for TBI.
Using a sophisticated tandem mass spectrometry (RPLC-MS/MS) platform developed by my colleague for simultaneously measuring multiple lipid mediators, we found that cultured neurons and astrocytes were unable to synthesize cyteinyl-leukotrienes (LTC4, LTD4, and LTE4) when stimulated with either a calcium ionophore or lipopolysaccharide (LPS). However, when the brain cells were cocultured with leukocytes specifically neutrophils, and then stimulated with a calcium ionophore, there was a marked production of LTC4. Neutrophils themselves were unable to make LTC4. Thus, it became apparent that the synthesis of cysteinyl-leukotrienes by brain cells required their interaction with an immune cell. Using Western blot analysis to identify the biosynthetic enzymes present in each cell type, Santiago confirmed that the production of leukotrienes is tightly regulated, and the expression of 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP), enzymes required for the first step in leukotriene synthesis, is restricted to leukocytes. AA released from the cell membrane of activated leukocytes is rapidly converted to LTA4 by 5-LO and FLAP. LTA4 is then transported out of leukocytes and taken up by either astrocytes or neurons and further metabolized to LTC4 by the enzyme LTC4 synthase. Unlike 5-LO and FLAP, LTC4 synthase is expressed in most tissues. Santiago’s in vitro studies indicated that brain cells are able to synthesize leukotrienes by a unique mechanism called transcellular biosynthesis.
Although this study was successful in answering our original question about whether brain cells could synthesize leukotrienes, I questioned the physiological significance of this pathway. Does transcellular biosynthesis of leukotrienes occur in the brain in vivo? Can leukotrienes produced by this mechanism contribute significantly to an inflammatory response? These questions are what steered me to the field of TBI!
Neutrophils are known to infiltrate the brain after a TBI. I reasoned that an experimental model of TBI could provide the answers to my questions. I began another collaborative study with Dr. Lauren Frey, a neurologist, who developed a novel fluid percussion injury (FPI) apparatus utilizing a picospritzer to deliver a very reproducible pulse of fluid against the intact dura through a small craniotomy made in the left parietal cortex. FPI resulted in both focal and diffuse cerebral injury. The predominant histopathological features were focal contusion in the ipsilateral cortex along with intraparenchymal hemorrhage, edema, and neutrophil infiltration. When we examined the control rats (treated like the injured rats with the exception of the fluid pulse), we were unable to detect leukotrienes by RPLC/MS/MS in the uninjured brain. However, after FPI, leukotrienes were rapidly produced at physiological levels in both brain hemispheres, although levels in the ipsilateral hemisphere were higher then those in the contralateral hemisphere. To determine if invading neutrophils contributed to leukotriene production in the brain after FPI, we depleted rats of neutrophils using vinblastine prior to FPI. The vinblastine treatment completely depleted circulating neutrophils, but only partially blocked leukotriene production in the ipsilateral hemisphere and had no effect on leukotriene production in the contralateral hemisphere. These results indicated two important things: firstly, circulating neutrophils contribute to injury-induced leukotriene production in the brain, and secondly, the brain has an endogenous source of the precursor LTA4 used for leukotriene production. Because 5-LO and FLAP are expressed by immune cells, we argued that the endogenous source of LTA4 must come from the brain’s resident immune cells, that is, microglia. We now believe that microglia are the first responders to damaged tissue after a TBI, and upon activation by the innate immune response, synthesize leukotrienes within minutes of injury that recruit additional immune cells and propagate inflammation.
To investigate the role of leukotrienes in the neuroinflammatory response to injury, we used inhibitors of FLAP to block leukotriene biosynthesis. Administration of an FLAP inhibitor before or shortly after FPI significantly reduced leukotriene production, edema, BBB permeability, and lesion size. It also mitigated deficits in synaptic plasticity and impairments in learning and memory. More recently, we have examined the role of leukotrienes in a closed head injury (CHI) model of mild TBI. In this model, administration of a FLAP inhibitor significantly reduced the number of activated microglia and reactive astrocytes present in the brain at a week and a month after CHI. It also reduced the number of degenerating neurons induced by CHI. These results and other studies, indicate that FLAP inhibitors are feasible therapeutic candidates to develop for TBI. The fact that MK-886 and MK-591, both off-patent drugs, were previously tested in human asthma trials and found to be efficacious in blocking leukotriene production and relieving asthma symptoms without toxicity makes them even more compelling therapeutic candidates for TBI.
So that is my story of how serendipity and multidisciplinary collaboration play an important role in driving research and drug discovery. I’m sure that all of the authors that contributed chapters for this book have their own stories to tell of what led them to investigate TBI. I want to thank all of them for taking time from their busy academic and medical professions to contribute to this book. I would also like to acknowledge the students and postdoctoral fellows who contributed to the research described in this book. Lastly, I would like to acknowledge Kathy Padilla and Melanie Tucker from Elsevier for their assistance with this book.
I would like to dedicate this book to all individuals who have sustained a TBI and to their caregivers. It is my hope that we will soon have a treatment that will stimulate restoration of the brain and prevent or reduce the damage that causes devastating neurologic impairments after a TBI.
Kim A. Heidenreich
Introduction
Traumatic brain injury (TBI) is a huge unmet medical need and a major cause of death and disability throughout the world. Public awareness of TBI has increased over the past decade due to the high incidence of TBIs in military personnel returning from conflicts in the Middle East and the recent reports of neurodegenerative brain pathology resulting from repetitive concussions. With the increased media coverage surrounding TBI, the public now realizes that concussions are serious injuries and that all types of TBI, regardless of severity, can result in life-long disabilities.
Although helmets, seatbelts, and other protective gear help to reduce brain injuries, there are over 1.7 million hospitalized TBI cases, and a much larger number of unreported TBI cases, per year in the United States. Falls and motor vehicle accidents are the major causes of reported TBIs. There are several injury phases following a TBI regardless of the severity of the insult (Fig. 1). The primary injury encompasses mechanical damage to the brain from shearing, tearing, or stretching forces. White matter (ie, myelinated axons) is particularly vulnerable to TBI; however, gray matter (ie, cell bodies) is also damaged following a TBI. The injured tissue releases signals called damage associated molecular patterns (DAMPs) including ATP and glutamate that activate pattern recognition receptors on microglia and astrocytes in situ and infiltrated peripheral immune cells to initiate the secondary injury phase. This phase of injury includes inflammation mediated by leukotrienes, cytokines, and chemokines; the generation of reactive oxygen species and excitotoxicity; mitochondrial impairment; and vascular dysfunction. These events underlie the postconcussive symptoms that result from a TBI and, if unresolved, can lead to life-long cognitive and behavioral disabilities and possibly dementia and suicide. Fortunately, the brain has a number of regeneration and repair mechanisms that are also activated during injury. These processes promote recovery and include neurogenesis, plasticity, re-myelination, and angiogenesis. Most individuals that sustain a concussion recover within 1–2 months after the event; however, a significant fraction (20–30%) of concussed patients do not recover within this timeframe and suffer a condition termed postconcussive syndrome (PCS). The underlying cause of PCS is not well understood but may involve an inability to interrupt the secondary injury phase or a failure to activate regeneration and repair processes.
An important aspect of the secondary injury phase is that it evolves over minutes to days to months after the primary injury. The delayed nature of secondary injury suggests that there is a therapeutic window for interventions that will prevent or mitigate this phase of injury or therapeutics that will stimulate regeneration and repair. A number of potential candidates have been discovered and proven efficacious in preclinical studies. Unfortunately, only a small number of these have made it to TBI clinical trials and those that did failed to show significance for their primary endpoint. A number of issues, including the absence of quantitative outcome measures to follow the efficacy of putative therapeutics, differences between preclinical models and the human condition, and the heterogeneity of brain injuries, have contributed to the difficulties in translating laboratory findings to the clinic.
Figure 1 Schematic of the response of the brain to injury and the secondary injury pathways that are activated by traumatic brain injury.
The drugs discussed in this book and where in the injury pathway they exert their effects are highlighted in blue.
The objective of this book is to inform physicians, researchers, TBI victims, and caregivers of new emerging therapeutics that show promise for preventing or mitigating secondary brain injury following a TBI. A second goal is to promote hope and incentive for testing new therapeutics and getting them to the patients that need them. The book begins with a discussion of the recent progesterone trials and other Phase III trials examining the therapeutic benefits of hypothermia and hyperbaric oxygen. These topics are followed by a discussion of a number of FDA approved drugs, including erythropoietin (EPO), atorvastatin, glibenclamide, and a TNF antagonist, which are being repurposed for TBI. The repurposing of drugs can potentially streamline the process in getting therapeutic drugs to the patient population. The next section of the book describes drugs and cell-based therapies currently in Phase I or II trials including the NOS inhibitor (VAS203), the combination study of propranolol and clonidine (DASH), and the use of mesenchymal stromal cells for TBI. This section is followed by a number of promising drugs in the preclinical phase of development including estradiol, voltage-gated calcium blockers, 5-lipoxygenase activating protein (FLAP) inhibitors, carbonyl scavengers, a TrkB receptor agonist, and ceftriaxone. As many of these drugs target different pathways of secondary brain injury, if advanced to clinical trials and proven efficacious, there is the potential of combining some of these drugs for even better therapeutic benefit in the future. The last section of this book describes drugs that are used to improve the lives of TBI patients in rehabilitation, including the NMDA antagonist, memantine, the anticholinesterase inhibitor, rivastigmine, DHA and 3-omegas, and psychotropic drugs.
It is our hope that the information in this book will provide strong rationale for intensifying research and increasing federal funding toward finding a treatment that will prevent or mitigate brain damage following a TBI and improve the lives of TBI patients.
Part I
Interventional Therapies for TBI Previously or Currently in Phase 3 Clinical Trials
Outline
Chapter 1. Why Did the Phase III Clinical Trials for Progesterone in TBI Fail? An Analysis of Three Potentially Critical Factors
Chapter 2. Hypothermia for Traumatic Brain Injury: Current Evidence and Future Directions
Chapter 3. The Future of TBI: Hyperbaric Oxygen as a Primary Therapeutic Approach
Chapter 1
Why Did the Phase III Clinical Trials for Progesterone in TBI Fail? An Analysis of Three Potentially Critical Factors
D.G. Stein¹, R.B. Howard², and I. Sayeed¹ ¹Emory University, Atlanta, GA, United States ²Emory University (Former), Atlanta, GA, United States
Abstract
Despite hundreds of positive preclinical studies and two successful Phase II clinical trials, two large Phase III trials of progesterone treatment for traumatic brain injury were recently ended with no finding of any difference between the test drug and placebo. This chapter discusses some possible reasons for this outcome and proposes returning to Phase II and using a more effective clinical trial design. Specifically, we propose dose and duration of treatment optimization following allometric scaling principles to convert rat mg/kg/day dose to the appropriate human dose. We also propose to verify that the vehicle, at the concentration needed for patients, does not have antiinflammatory or neuroprotective clinical effects. Finally, preclinical animal studies should be conducted to determine whether the lipid vehicles used might alter the drug effects at the required concentrations.
Keywords
Allometric scaling; Progesterone; ProTECT III; SyNAPSe; Traumatic brain injury
Introduction: Progesterone Treatment Showed Promise in Preclinical Research
Although in many animal models of CNS injury, acute-stage treatment with progesterone demonstrated multifactorial benefits in the repair of the damaged brain, the Phase III translation to effective clinical outcome was disappointing. Over 300 preclinical studies listed on PubMed in both male and female subjects demonstrate that, given within the first few days after a traumatic brain injury (TBI), progesterone can modulate the expression of inflammatory cytokines, reduce levels of glutamate toxicity, attenuate both vasogenic and intracellular cerebral edema, prevent apoptosis and necrosis, restore the functions of the blood–brain barrier, and improve functional outcomes on sensory, cognitive, and motor behaviors. At the cellular level, giving progesterone early in the injury cascade can stimulate glial cells to increase myelin formation and restore metabolic function through its effects on the mitochondrial transition pore, and modify calcium channel activity to stabilize cellular metabolism, reducing the cytochemical cascade that can lead to further cell death in the days, weeks, and months after injury.
Progesterone is also known to have growth-promoting properties in the central nervous system. In preclinical experiments, it stimulates the expression and release of neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor, which repair the damaged brain by stimulating neurogenesis, protecting against axonal degeneration, and enhancing synaptogenesis. Many genes involved in the expression of trophic factors and the inhibition of inflammatory cytokines can be regulated by progesterone, because it works through multiple receptor mechanisms throughout the brain. In laboratory experiments, progesterone and its metabolites consistently produce these beneficial effects in the brain and spinal cord after traumatic contusion injuries, nerve crush injuries, diffuse axonal injury, stroke, hemorrhage, cytotoxic injury, and even in degenerative neuropathologies. For a more detailed understanding of how progesterone and its metabolites modulate the cascade of mechanisms leading to both neuronal loss and repair over the course of brain insult, see Arevalo, Santos-Galindo, Acaz-Fonseca, Azcoitia, and Garcia-Segura (2013), De Nicola, Coronel, et al. (2013), Guennoun et al. (2015), Johann and Beyer (2013), Melcangi et al. (2013), Schumacher et al. (2014), and Stein (2013).
Despite a few reports in the preclinical literature showing no benefits of progesterone treatment (Gilmer, Roberts, & Scheff, 2008; Spratt, Tomkins, Pepperall, McLeod, & Calford, 2014; Wong, Gibson, Kendall, & Bath, 2014), with no known toxic effects and so much experimental data supporting its neuroprotective properties, why did this well-known and well-established drug show no translational promise in Phase III clinical trials?
The Phase II Trials
About 10 years ago, two small, single-center clinical trials began to test progesterone in patients with moderate to severe TBI. ProTECT II (Wright et al., 2007) was a randomized, double-blind, placebo-controlled trial that enrolled consenting adult patients of both sexes within 11 h after their injuries with moderate-to-severe Glasgow Coma Scores (GCS) of 4–12 (detail in Table 1.1). A lower GCS score indicates a lower level of consciousness; the best score, 15, represents the best possible outcome.
Patients received standard of practice care plus or minus progesterone treatment by continuous i.v. infusion at 12 mg/kg/day for 3 days in Intralipid vehicle. The frequency of serious adverse events (SAEs) and mortality at 30 days postinjury were the measures of drug safety. The primary measure of functional benefit, also measured only at 30 days post-TBI, was the dichotomized Glasgow Outcome Scale-extended (GOS-E). The Disability Rating Scale (DRS), another quality of life rating-scale measure, was also used. No SAEs were attributable to the progesterone treatment. At 30 days after injury, the progesterone-treated patients with severe TBI (GCS 4–8) remained in coma longer but had a significantly lower mortality compared to patients given only Intralipid. However, upon emerging from their comas, these same patients had somewhat worse GOS-E and DRS scores compared to controls. The investigators speculated that the drug may have increased the incidence of survival in a badly injured treated subpopulation who probably would have died if they had been in the control group. In contrast, the moderately injured (GCS 9–12) TBI patients given progesterone had significantly better 30-day outcomes on the GOS-E and DRS than the placebo group.
Table 1.1
Phase II Trials
a Wright et al. (2007).
b Xiao et al. (2008).
Although these findings seemed promising, trial authors were careful to note that ProTECT II was conducted only at one site, with a 4:1 treatment:placebo ratio, and functional outcomes and mortality were evaluated only at 30 days postinjury using very limited, mostly qualitative tests that, as noted by a National Institutes of Health (NIH) expert consensus panel, can miss clinically important findings that may be detectable by more sophisticated neuropsychological tests
(Hannay, Exrachi, Contant, & Levin, 1996). It is worth noting also that the primary purpose of this first trial was to assess safety, not efficacy. ProTECT II did not study any biomarkers or any dose escalation, duration-of-treatment, or treatment-delay parameters.
Shortly after ProTECT II was started, a Phase II, 1:1 randomized trial performed at a hospital in Hangzhou, China (Xiao, Wei, Yan, Wang, & Lu, 2008) began enrolling 159 male and female adult patients with only severe TBI (GCS 3–8). Blinded treatment with progesterone or vehicle was