Progesterone, Vitamin D, and the Acute Inflammatory Response After Traumatic Brain Injury in the Aged Rat Público

Abstract

Traumatic brain injury (TBI) is the greatest single cause of death for people in the
Western world younger than 45 and a significant cause of death and disability worldwide.
The past decade has also seen a 21% increase in TBI events in people over the age of 65,
with the mortality rate in this age group more than twice that of young adults. A large
amount of recent evidence has shown that treatment with the neuroactive steroid
progesterone (PROG) can attenuate many of the pathophysiological events following TBI
in young adult animals as well as human patients, but this has not been specifically
investigated in the aged. In this series of studies, we extend the potential application of
progesterone (PROG) as a treatment for TBI to older subjects by demonstrating its
effectiveness in reducing acute inflammation, cell death, and cerebral edema, and
improving short-term behavioral outcome in aged rats after bilateral frontal cortical
contusion injury. We also show that vitamin D deficiency, which is virtually endemic in
the elderly population in industrialized countries and is associated with a number of
systemic problems such as cardiovascular disease, atherosclerosis, and cancer, increases
baseline inflammation prior to injury, exacerbates the acute inflammatory response to the
injury itself, and attenuates the beneficial effects of PROG treatment after TBI in aged
rats. These effects can be overcome by co-administration of PROG with 1,25-
hydroxyvitamin D3 (vitamin D hormone, VDH), the biologically active form of vitamin
D and a neuroactive seco-steroid. Since TBI is a complex process affecting the entire
organism and not just the nervous system, with the most common proximate causes of
death after injury being edema, sepsis, or overwhelming systemic inflammation leading
to multi-organ failure, these results have direct translational implications for treatment
and early survival in the elderly human population with brain injury. We show that the
endogenous systemic hormonal environment can affect brain injury and treatment
outcome, and suggest that combination therapies, especially with pleiotropic agents that
affect partially overlapping mechanisms, may be better suited than single targeted agents
to the treatment of heterogeneous disease processes such as human TBI.

Table of Contents

CHAPTER 1: INTRODUCTION.............................................................................1

1.1. GENERAL INTRODUCTION..................................................................1

1.2. HYPOTHESES, EXPERIMENTAL DESIGN, AND ORGANIZATION................10

CHAPTER 2: TRAUMATIC BRAIN INJURY AND AGING...........................................14

2.1. ABSTRACT......................................................................................14

2.2. TRAUMATIC BRAIN INJURY: OVERVIEW..............................................15

2.3. AGING: OVERVIEW..........................................................................41

CHAPTER 3: PROGESTERONE AND TRAUMATIC BRAIN INJURY..............................51

3.1. ABSTRACT......................................................................................51

3.2. PROGESTERONE AND TRAUMATIC BRAIN INJURY: OVERVIEW...............52

CHAPTER 4: PROGESTERONE IMPROVES ACUTE RECOVERY AFTER

TRAUMATIC BRAIN INJURY IN THE AGED RAT....................................................66

4.1. ABSTRACT......................................................................................66

4.2. INTRODUCTION..............................................................................67

4.3. MATERIALS AND METHODS...............................................................71

4.4. RESULTS........................................................................................76

4.5. DISCUSSION..................................................................................90

CHAPTER 5: VITAMIN D DEFICIENCY REDUCES THE BENEFITS OF

PROGESTERONE TREATMENT AFTER BRAIN INJURY IN AGED RATS.......................96

5.1. ABSTRACT......................................................................................96

5.2. INTRODUCTION..............................................................................97

5.3. MATERIALS AND METHODS.............................................................100

5.4. RESULTS.......................................................................................105

5.5. DISCUSSION.................................................................................123

CHAPTER 6: COMBINATION TREATMENT WITH PROGESTERONE AND VITAMIN D

HORMONE MAY BE MORE EFFECTIVE THAN MONOTHERAPY FOR NERVOUS

SYSTEM INJURY AND DISEASE.......................................................................126

6.1. ABSTRACT.....................................................................................126

6.2. INTRODUCTION.............................................................................127

6.3. VITAMIN D AND NEUROPROTECTION................................................130

6.4. WHY COMBINE VITAMIN D AND PROGESTERONE?..............................146

6.5. CONCLUSION................................................................................152

CHAPTER 7: PROGESTERONE AND 1.25-DIHYDROXYVITAMIN D3 IMPROVE

OUTCOME IN YOUNG AND VITAMIN D DEFICIENT OLD RATS WITH

BRAIN INJURY..............................................................................................154

7.1. ABSTRACT.....................................................................................154

7.2. INTRODUCTION.............................................................................156

7.3. MATERIALS AND METHODS..............................................................159

7.4. RESULTS.......................................................................................164

7.5. DISCUSSION.................................................................................184

CHAPTER 8: CONCLUSIONS, IMPLICATIONS, AND FUTURE DIRECTIONS...............189

8.1. ABSTRACT.....................................................................................189

8.2. GENERAL SUMMARY AND CLINICAL IMPLICATIONS.............................190

8.3. POTENTIAL UNDERLYING MECHANISMS.............................................203

8.4. CLOSING REMARKS AND FUTURE DIRECTIONS...................................215

REFERENCES................................................................................................217

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Health Sciences, Medicine and Surgery
Palabra Clave	Progesterone Traumatic brain injury Aging Vitamin D deficiency 1,25-dihydroxyvitamin D3 Inflammation
Committee Chair / Thesis Advisor	Stein, Donald G, Emory University
Committee Members	Wright, David W, Emory University McKeon, Robert, Emory University Pettus, Edward, Emory University DeLong, Mahlon R, Emory University

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