Progesterone, Vitamin D, and the Acute Inflammatory Response After Traumatic Brain Injury in the Aged Rat Público
Cekic, Milos (2011)
Published
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
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