Estrogen Effects on Traumatic Brain Injury

Mechanisms of Neuroprotection and Repair

Kelli A Duncan

• Publisher: Academic Press
• Year: 2014
• Print ISBN: 9780128014790
• eBook ISBN: 9780128017074
• Topic: Medicine
• Subtopic: Neurology

This book demystifies, deconstructs, and simultaneously humanizes the field of estrogen-mediated neuroprotection following TBI, making the subject approachable to both researchers and advanced students. Bringing together leading researchers and practitioners to explain the basis for their work, methods, and their results, chapters explore what is known about the role of estrogens following damage to the brain. With topics covering induction of estrogen response, consequences of estrogen action, and mechanisms underlying estrogen mediated neuroprotection, Estrogen Effects on Traumatic Brain Injury is of great importance to teachers, researchers, and clinicians interested in the role that estrogens play following traumatic brain injury. - Written to provide a foundational view of estrogens as neuroprotectors in TBI, appropriate for both researchers and advanced students - Data Analysis boxes in each chapter help with data interpretation and offer guidelines on how best to understand results - A multidisciplinary approach to the methods, issues, empirical findings in the field of estrogen mediated neuroprotection - Detailed focus on how studies relate and build upon each other and the ways different methods of analysis inform each other - Written to provide clinicians with new and developing treatment options for patients in their field

Chapter 1

Historical Antecedents

John P. Hayden, Biology, Vassar College, Poughkeepsie, New York, USA

The study of traumatic brain injury has exploded over the last 25 years. Within this chapter we will introduce the current terminology, general history, and current research trends of traumatic brain injury. First, we will describe the types of brain injuries to be discussed in this book. Next, we will examine the historical antecedents in the study and treatment of traumatic brain injury, from antiquity to now. Finally, we will close with a brief overview of the current treatment options following traumatic brain injury including sex differences in traumatic brain injury and the use of steroid hormones including estrogens as a treatment option.

Keywords

traumatic brain injury; blunt force trauma; penetrating injury; hypoxic ischemic injury; steroid hormones; estrogens

Introduction

On September 13, 1848, 25-year-old Phineas Gage arrived at the doorstep of Vermont physician Dr. John Harlow after an accidental explosion at a railroad construction site had catapulted a 1-meter long, 6-kg iron tamping rod into Gage’s cheek, through his brain, and out the top of his skull (Kotowicz, 2007; Figure 1.1). Incredibly, the young man had not lost consciousness, and was lucid enough to recount the tale to a likely dumbfounded Harlow. The improbable story of Phineas Gage, a favorite among neuroscientists, has become infamous. From the shocking lack of immediate symptoms to the accounts of drastic personality change and recovery, all aspects of his tale grip our imaginations and probe us to ask the question:

Figure 1.1 Images of Phineas Gage based upon three figures from Harlow’s 1868 paper. A) Depicts the angle of the rod through Phineas Gage’s head. B) Image depicting the damage and injury tract to Phineas Gage’s skull and frontal lobe following the accident.

How did Phineas Gage survive such a horrific brain injury?

It has now been more than 150 years since Gage’s accident, and we are still learning about the consequences of trauma to the brain. In this chapter, we will explain the most recent definitions of traumatic brain injury (TBI), and explore how our understanding of TBI and its effective treatment have changed from ancient times to the 21st century. Finally, we will examine how both basic scientists and clinicians have revolutionized how we treat the brain. In particular, we will focus on the role of steroid hormones, specifically estrogens, as effective tools in the current management of TBI.

The “INS AND OUTS” of TBI: An Overview

Not all injuries that inflict trauma to the brain are the same. For this reason, our understanding of modern TBI terminology will begin with an explanation of three broad categories, which we will use to divide the injuries by mechanisms of assault (Table 1.1). The most common category of injury is blunt force trauma or “closed-head injury.” Blunt force trauma often presents as a concussion, intracranial hematoma, cerebral contusion, or a diffuse axonal injury. Despite serious damage to the brain, skull and dura mater remain physically intact. Examples of blunt force injuries include vehicular accidents, falls, acts of violence, and sports injuries. Blunt force trauma can range from single/multiple mild incidents (as observed in most sports-related injuries) to more severe blast-related incidents (as observed in recent veterans of the various wars in the Middle East). These types of injuries can result in major neurological and/or cognitive deficits or even fatality (Reilly and Bullock, 2005; Taber et al., 2006).

Table 1.1

Categories of Traumatic Brain Injury

	Definition	Possible symptoms	Clinical examples
Blunt Force Trauma	Non-penetrating impact to head	Concussion, intracranial hematoma, cerebral contusion, diffuse axonal injury, neurological and/or cognitive deficits	Vehicular accidents, falls, acts of violence, and sports injuries
Penetrating Injury	Damage that results from a foreign object penetrating the nervous tissue	Shear-like injury to neurons, epidural hematomas, subdural hematomas, parenchymal contusions	Gun shot wounds, stabbing
Hypoxic-ischemic brain injury	Damage caused by a reduction in oxygen and/or diminished blood supply	Seizures, disturbances of sensorimotor function, neuronal death, neurological and/or cognitive deficits	Cardiac arrest, respiratory arrest, near-drowning or hanging, carbon monoxide exposure, and perinatal asphyxia

The second category of injury, penetrating injury, occurs when a foreign object pierces the nervous tissue, specifically the brain, causing localized damage along the path of entry (Reilly and Bullock, 2005). The most common presentations of a penetrating injury are related to gun violence and stabbings. In the case of penetrating injuries, both the skull and the dura mater are damaged. Penetrating injuries can result in shear-like injury to the neurons, epidural hematomas, subdural hematomas, or parenchymal contusions. Though less common than blunt force trauma, penetrating injuries carry a far worse prognosis (Kazim et al., 2011). While these first two categories are useful tools in qualifying injuries beyond “head trauma,” they are not mutually exclusive. It is entirely possible for a single accident to result in both blunt force and penetrating injuries. After the iron rod shot through Gage’s skull, he fell to the ground, and it is very likely that, in addition to the damage caused by the rod, a secondary impact occurred. In cases like this, the brain would exhibit both localized and global injuries from the penetrating and blunt force injuries, respectively.

The final category of TBI that will be explored in this book is not caused by forces against the brain at all but instead is the result of decreased glucose and oxygen. Hypoxic-ischemic brain injury is any injury to the brain induced by hypoxia (reduction in oxygen) and ischemia (diminished blood supply; Busl and Greer, 2010). The typical causes of hypoxic-ischemic brain injury include cardiac arrest, respiratory arrest, near-drowning or hanging, carbon monoxide exposure, and perinatal asphyxia, and resulting symptoms include seizures, disturbances of sensorimotor function, neuronal death, and neurological and/or cognitive deficits (Busl and Greer, 2010).

Beyond these rudimentary classifications, two distinct stages of injury occur within all three mechanical subtypes of TBI (Table 1.2). The first stage of damage is referred to as the primary injury because it occurs at the time of assault and is the direct result of trauma to the brain (Reilly and Bullock, 2005). This initial trauma can include lacerations, contusions, hematomas, sheared neurons, and fractures of the skull (Marion, 1999). Because the primary injury is only defined by the initial physical trauma, any symptoms of the primary injury may be immediately apparent following assault. Phineas Gage was able to get up and walk away from his accident with relatively minor impairment because his primary injuries miraculously did not cause enough physical damage to impinge on his basic bodily functions. Nerves and tissue had certainly been damaged, but likely manifested their trauma in less severe symptoms such as nausea, dizziness and transient loss of consciousness.

Table 1.2

Definition and Components of Two Stages of Traumatic Brain Injury

	Definition	Components
Primary Injury	Trauma to the brain that is localized to the site of injury, and occurs at the time of assault	Tearing, shearing and rupturing of blood vessels, direct damage to brain tissue, neurons and blood–brain barrier
Secondary Injury	Slowly developing damage that results from biochemical and physical responses to the initial trauma	Ischemia, hypoxia, cerebral edema, oxidative damage, glucose starvation, acidosis

Gage’s incredible resilience was only temporary, however, and following the accident his mental and physical health declined. The apparent discontinuity between his acute and chronic symptoms was likely caused by the onset of the next stage of TBI, the secondary injury. The secondary injury develops in the aftermath of assault, and includes various detrimental biochemical and physical changes within the brain (Coetzer, 2006). In contrast to the primary injury, the damage caused by secondary injury develops slowly, worsening in the aftermath of the assault. Deviations from normal physiological levels of acetylcholine and free radicals in the brain can combine with other biochemical changes to restrict cerebral blood flow following injury (Coetzer, 2006). Further restriction may also result from pro-inflammatory pathways that cause an increase in neurodegenerative properties, such as edema. As the brain expands beyond its normal volume, it may also press itself against the rigid boundaries of the skull, resulting in both increased intracranial pressure (ICP), and additional restriction of blood flow (Coetzer, 2006). The ischemia caused by this reduction causes a damaging deficit in the amount of oxygen and glucose that are available to the brain. These various effects compound one another, and result in increased damage to the brain. For Gage, it is very possible that his symptoms were exacerbated in the days following his injury by increasing edema, ischemia, and axonal injury. Over the course of several days, an injury that once allowed Gage to immediately rise to his feet and speak with the doctor likely became much worse, and eventually Gage’s own body would have left itself with a more severe injury than was initially caused by the rod.

Gage’s reported decline following his injury highlights the critical component of the secondary injury that makes it so important to contemporary TBI research. The secondary injury represents the “access point” that doctors have to limit the amount of damage that occurs following injury. While the ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• About the Editor
• List of Contributors
• About the Contributors
• Introduction
• Chapter 1. Historical Antecedents
• Chapter 2. Estrogen Actions in the Brain
• Chapter 3. Induction of Estrogen Response Following Injury
• Chapter 4. Astrocytic Aromatization and Injury
• Chapter 5. Aromatase and Estrogens: Involvement in Constitutive and Regenerative Neurogenesis in Adult Zebrafish
• Chapter 6. Neuroprotection by Exogenous Estrogenic Compounds Following Traumatic Brain Injury
• Chapter 7. Neuroprotective Effects of Estrogen Following Neural Injury
• Chapter 8. Neuroprotection with Estradiol in Experimental Perinatal Asphyxia: A New Approach
• Chapter 9. Cerebrovascular Stroke: Sex Differences and the Impact of Estrogens
• Chapter 10. Concluding Statements and Current Challenges
• Index