Type of Document	Thesis
Author	Figueiroa da Cruz, Silvia S. M.
URN	etd-11042008-224537
Title	Efficacy of Vitamin D3 and Progesterone Interactions Following Traumatic Brain Injury
Degree	Master of Science
Department	Nutrition, Food, and Exercise Science, Department of
Advisory Committee	Advisor Name Title Cathy W. Levenson Committee Chair Jasminka Ilich-Ernst Committee Member Robert J. Contreras Outside Committee Member
Keywords	TBI Traumatic Brain Injury Brain Trauma Neuroprotection Vitamin D Progesterone Edema PXR MRI Neurosteroids
Date of Defense	2008-10-20
Availability	unrestricted
Abstract The health care and quality of life costs of traumatic brain injury (TBI) are growing annually. This is in part due to the fact that the effectiveness of the current treatments for TBI is limited. Recent work in animal models as well as clinical trials, has identified a positive role for the hormone progesterone in the treatment of TBI. Thus, this work sought to build on that observation and test the central hypothesis that the hormonally active form of vitamin D could be useful as an adjunct to progesterone treatment after medial frontal cortex contusion. To test this hypothesis, we first used direct measurements of water accumulation as the site of injury to examine the extent to which vitamin D acts to reduce edema associated with TBI. We also employed two forms of (standard proton and diffusion-weighted) high strength magnetic resonance imaging (900 MHz) to develop the methodology to make long term measurements of water accumulation and the effectiveness of interventions after TBI. The results from these combined methodologies suggest that vitamin D is an effective adjunct to treatment with progesterone by reducing acute edema that is frequently associated with poor long-term behavioral outcomes. Our initial attempts to identify the mechanisms responsible for the synergistic effect of vitamin D and progesterone included measurement of a number of proteins in and around the site of injury that are known to regulate the action of steroid hormones and water accumulation in the brain. Interestingly, neither injury nor treatment altered the expression of aquaporin-4 (AQP-4), glucose-6-phosphate dehydrogenase (G6PD), and 25-hydroxyvitamin D 24-hydroxylase (CYP24). However, there was a 3-fold increase in the progesterone receptor pregnane X (PXR) and in the Multidrug resistance-1 (MDR-1) observed with progesterone treatment compared to sham. These increases were suppressed by vitamin D3 treatment, suggesting a role for vitamin D3 as a PXR antagonist. In contrast, tumor necrosis factor-á expression, which is linked to inflammation, was elevated by the combination therapy. These results suggest that vitamin D may have a role in reducing edema at the site of injury; nevertheless, future work will be needed to identify the cellular and molecular mechanisms responsible for this observation and determine the impact of possible side effects such as enhanced inflammatory processes.
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