New Therapeutics for Traumatic Brain Injury

Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration

1st Edition - September 27, 2016
Editor: Kim Heidenreich
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 0 2 6 8 6 - 1
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 2 7 0 1 - 1

New Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration explores traumatic brain injury (TBI), a major cau… Read more

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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.

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

Kim Heidenreich

Kim A. Heidenreich is Professor of Pharmacology and Neuroscience at the University of Colorado School of Medicine. She also serves on the Keystone Scientific Advisory Board and is Chief Scientific Advisor for the American Traumatic Brain Injury Association. Dr. Heidenreich has been conducting neuroscience research for over 30 years with continual funding in the area of neurotrophic factors, mechanisms of neuronal cell death, and recently, traumatic brain injury (TBI). Her laboratory has identified a number of protein kinase signaling pathways that trigger or prevent neuronal cell death in response to neuronal insults and neurotrophic factors, respectively. She has examined the ways in which key proapoptotic and antiapoptotic protein kinases regulate cytoplasmic, mitochondrial, and nuclear targets to control neuronal apoptosis and autophagy. Her recent studies have focused on preventing secondary brain damage after a TBI. She has recently discovered that leukotrienes, potent inflammatory lipid mediators normally absent in brain, are produced by a transcellular mechanism involving infiltrating neutrophils after TBI. Blockade of leukotriene production using 5-lipoxgenase (FLAP) inhibitors prevents edema, cell death, and cognitive deficits after TBI. These findings have important implications for treating human TBI and suggest that development of FLAP inhibitors for use in TBI is feasible for both intervention and prevention. Toward this goal, Dr. Heidenreich is currently developing FLAP inhibitors with improved CNS properties and novel delivery methods for these drugs in TBI.

As a strong advocate of Neuroscience research, Dr. Heidenreich has previously served as chair of the membership committee of the UC Denver Neuroscience Program and as President of the Rocky Mountain Neuroscience Research Group, a Colorado chapter of the Society of Neuroscience. She has mentored many pre- and post-doctoral scientists, as well as junior physician scientists, in her laboratory. She also has served as mentor for the NIH Building Research Achievement in Neuroscience (BRAiN) Training Program and was the recipient of the 2006 Dean’s Mentoring Award at her institution. Dr. Heidenreich has served on numerous study sections reviewing grants for the NIH, DOD, VA and small research granting agencies. Recently, she has been invited to speak at numerous national and international TBI conferences including the Annual Traumatic Brain Injury Conference in Washington, D.C. and the C4CT Concussion Awareness Summits, the last one held Pre-superbowl 2014 at the United Nations. She has been a recipient of research support from the State of Colorado Brain Injury Program for the past five years. Dr. Heidenreich received her undergraduate degree in Biology from Westminster College in 1974 and her Ph.D. in Physiology/Biophysics from the University of Vermont in 1979.

Affiliations and expertise

University of Colorado Denver School of Medicine, Aurora, Colorado, USA

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health