15
Vitamin D

The requirement for the essential nutrient vitamin D can be met by a combination of de novo synthesis and intake, either from dietary sources or supplements. The form of vitamin D derived from plant sources is D2, while D3 is the form derived from the intake of animal-based foods. Vitamin D3 also can be synthesized from cholesterol by exposure of the skin to ultraviolet light. Both of these forms of vitamin D act as prohormones. Modified first by the liver enzyme 25-hydroxylase, vitamin D is then transported to the kidney microsomes where it is converted to the active hormonal form known as 1,25-dihydroxyvitamin D, or calcitriol.

The function of the hormonal form of vitamin D is mediated by the nuclear receptor vitamin D receptor (VDR), which acts as a DNA-binding protein to regulate the transcription of vitamin D–responsive genes. This mechanism of action is responsible for enhanced intestinal calcium absorption, kidney calcium reabsorption, and bone resorption of calcium. In this way, vitamin D regulates serum calcium and phosphate levels as well as bone metabolism. Although vitamin D’s role in calcium balance is most prominent in the literature, it is clear that vitamin D also plays a key role in the molecular processes that control cellular proliferation, differentiation, and survival (Fleet, 2007). Consequently, in addition to the development of rickets and osteopenia, vitamin D deficiency has been linked to a variety of illnesses including hypertension and heart disease, obesity, diabetes, rheumatoid arthritis, and an increased risk of cancer (Holick, 2007; Martini and Wood, 2008; Wood, 2008).

VITAMIN D AND THE BRAIN

Although the role of vitamin D in calcium absorption, serum calcium balance, and bone metabolism has long been recognized, its essential role in the brain and central nervous system (CNS) has only recently been appreciated. It is now known that the human brain expresses the enzyme 1 alpha-hydroxylase, responsible for the hydroxylation of 25-hydroxyvitamin D to its active, hormonal form, 1,25-dihydroxyvitamin D; as well as the nuclear receptor for vitamin D, VDR.



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15 Vitamin D The requirement for the essential nutrient vitamin D can be met by a combination of de novo synthesis and intake, either from dietary sources or supplements. The form of vitamin D derived from plant sources is D2, while D3 is the form derived from the intake of animal- based foods. Vitamin D3 also can be synthesized from cholesterol by exposure of the skin to ultraviolet light. Both of these forms of vitamin D act as prohormones. Modified first by the liver enzyme 25-hydroxylase, vitamin D is then transported to the kidney microsomes where it is converted to the active hormonal form known as 1,25-dihydroxyvitamin D, or calcitriol. The function of the hormonal form of vitamin D is mediated by the nuclear receptor vitamin D receptor (VDR), which acts as a DNA-binding protein to regulate the transcrip- tion of vitamin D–responsive genes. This mechanism of action is responsible for enhanced intestinal calcium absorption, kidney calcium reabsorption, and bone resorption of calcium. In this way, vitamin D regulates serum calcium and phosphate levels as well as bone metabo- lism. Although vitamin D’s role in calcium balance is most prominent in the literature, it is clear that vitamin D also plays a key role in the molecular processes that control cellular proliferation, differentiation, and survival (Fleet, 2007). Consequently, in addition to the development of rickets and osteopenia, vitamin D deficiency has been linked to a variety of illnesses including hypertension and heart disease, obesity, diabetes, rheumatoid arthritis, and an increased risk of cancer (Holick, 2007; Martini and Wood, 2008; Wood, 2008). VITAMIN D AND THE BRAIN Although the role of vitamin D in calcium absorption, serum calcium balance, and bone metabolism has long been recognized, its essential role in the brain and central ner- vous system (CNS) has only recently been appreciated. It is now known that the human brain expresses the enzyme 1 alpha-hydroxylase, responsible for the hydroxylation of 25-hydroxyvitamin D to its active, hormonal form, 1,25-dihydroxyvitamin D; as well as the nuclear receptor for vitamin D, VDR. 227

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228 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 15-1 Relevant Data Identified for Vitamin D Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials None found Tier 2: Observational studies Buell Stroke Prospective 25(OH)D insufficiency (10–20 ng/mL) was associated with twice the risk of stroke (ORb=2.29, 95% CIc: et al., cohort study 2010 (Nutrition 1.09–4.83, p=0.03). But the association with stroke was and Memory not significant after stratifying for presence or absence of in Elders) dementia. Compared to patients taking sufficient levels (> 20 ng/ na=318 patients ≥ 60 mL) of 25(OH)D, deficient (< 10 ng/mL) patients had years old higher geometric mean white matter hypersensitivity (WMH) volume (p=0.004), higher WMH grade (p=0.02), and higher prevalence of large vessel infarcts (p < 0.01). Tier 3: Animal studies None found a n: sample size. b OR: relative risk. c CI: confidence interval. Although the roles of vitamin D in the CNS are not well understood, it appears that its function is largely mediated by VDR. This member of the steroid-thyroid nuclear receptor family is widely expressed in both the human and rodent cortex, spinal cord, amygdala, hypothalamus, cerebellum, mesopontine area, and diencephalon. VDR is particularly high in the hippocampus, a region of the brain associated not only with learning and memory, but also with emotion (Eyles et al., 2005). When the hormonal form of vitamin D associ- ates with VDR in the nucleus, this complex can combine with the retinoic acid receptor RXR to produce heterodimers. Together, these two nutrients (vitamin D in the form of 1,25(OH)2-D3 and vitamin A in the form of 9-cis-retinoic acid) and their respective nuclear receptors (VDR and RXR) bind to specific sequences of DNA known as vitamin D response elements (VDREs). Binding of this complex to VDREs in the 5′-flanking region of vitamin D–responsive genes results in the regulation of gene transcription in the CNS, where it is now believed to participate in cell proliferation and neuronal differentiation and neuronal function (Levenson and Figueirôa, 2008). Table 15-1 includes limited supporting evidence (1990 and later) from human studies on vitamin D supplementation for CNS injuries. Any adverse effects in humans are also listed. USES AND SAFETY The current Recommended Dietary Allowance (RDA) for vitamin D is 600 International Units (IU) per day for both male and female adults up to the age of 70 (IOM, 2010). At age 70, the RDA increases to 800 IU. There are a number of considerations to take into ac- count when applying these recommendations to military populations and others at risk for

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229 VITAMIN D traumatic brain injury (TBI). First, the current RDAs for vitamin D were developed under conditions of minimal sun exposure (IOM, 2010), and therefore do not factor in the vita- min D synthesized in the skin through exposure to sunlight. More importantly, the Institute of Medicine (IOM) set the current RDA for vitamin D at a level found to be sufficient to maintain bone health and normal calcium metabolism in healthy people, the only outcome found to be associated with vitamin D status. It is not known whether the dietary vitamin D requirement for optimal brain function under normal or injured conditions should be different. Median estimates of vitamin D intake from foods are below the Estimated Average Re- quirements (EARs) of 400 IU recently established by the IOM. However, vitamin D also is synthesized in the skin, and therefore vitamin D status is not accurately reflected exclusively by dietary intake. Using National Health and Nutrition Examination Survey (NHANES) data from 2000 to 2006, levels of 25-hydroxyvitamin D in serum, a depiction of total vita- min D exposure, were above 50 nmol/mL, the level identified as meeting the needs of most of the population. The IOM concluded that the population of North America, with the possible exception of the aging population and those with dark skin, is meeting its needs for vitamin D. NHANES (2005–2006) data show that 37 percent of the U.S. population reported us- ing vitamin D supplements. This is likely to be predominantly in the form of multivitamin supplements or as an adjunct to calcium supplementation. The current Tolerable Upper Intake Level (UL) for adults is 4,000 IU. Excess dietary intake of vitamin D has been shown to cause vitamin D intoxication, which leads to hypercalcemia and, eventually, soft tissue calcification and resultant renal and cardiovascular damage. EVIDENCE INDICATING EFFECT ON RESILIENCE Human Studies There have been no clinical trials to address the possibility that vitamin D supple- mentation may promote resilience to subsequent TBI. However, human data (in elderly populations) does indicate that failure to maintain adequate vitamin D nutriture is associ- ated with diminished neurocognitive health. For example, plasma 25-hydroxy vitamin D concentrations of less than 20 ng/mL in individuals 65–99 years of age were associated with increased prevalence of dementia, and concentrations below 10 ng/mL were associ- ated with increased cranial indicators (detected via magnetic resonance imaging [MRI]) of cerebrovascular disease such as white matter hyperintensity volume and large vessel infarcts (Buell et al., 2010). Animal Studies Maintaining adequate vitamin D nutrition prior to injury may be critical for post-TBI treatment with progesterone, the only agent that has thus far shown therapeutic benefit in randomized, placebo-controlled clinical trials. This possibility is based on a 2009 study conducted in aged rats (Cekic et al., 2009): vitamin D–replete animals showed a 50 percent reduction in spontaneous locomotor activity following contusion to the medial frontal cor- tex, but progesterone treatment fully restored activity. Rats deficient in vitamin D exhibited a similar reduction in locomotor activity following contusion, but treatment with either progesterone alone or vitamin D alone had no restorative effect. Although treatment with progesterone plus vitamin D did completely restore locomotor activity, the possible efficacy

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230 NUTRITION AND TRAUMATIC BRAIN INJURY of vitamin D as an adjunct to progesterone therapy is supported by in vitro data showing that pretreatment of cultured rat cortical neurons with either progesterone or vitamin D protected the cells from glutamate-induced excitotoxicity. Pretreatment with progesterone in combination with some lower doses of vitamin D was more protective than progesterone alone (Atif et al., 2009). This requirement for vitamin D is important in light of two very encouraging human studies involving progesterone. In the first, Wright and colleagues (2007) conducted a phase II clinical trial with TBI patients. The treated patient group achieved a significantly lower mortality rate at 30 days and improved scores on disability rating scales at 30 days and 1 year postinjury, compared to the placebo-treated patients; there were no serious adverse events observed. In the second study, Xiao and coworkers (2008) performed a human trial involving patients with severe TBI. These patients had significantly improved functional independence and Glasgow Outcome Scale scores at three and six months postinjury, and lower mortality at six months, compared to placebo-treated controls. Progesterone admin- istration to patients with severe TBI is currently in phase III clinical trials. Progesterone is best known as a steroid hormone involved in the regulation of reproduc - tive function (Cannon, 1998), and in immunosuppression during pregnancy to guard against immunological rejection of the fetus (Arck et al., 2007). Progesterone is, however, also pro- duced in the cerebral cortex, hypothalamus, and other areas of the brains of both men and women, primarily by astrocytes (Micevych and Sinchak, 2008); receptors for progesterone are also located in the brain, many in regions associated with cognitive function (Wagner, 2008). There is growing evidence that neuroprogesterone produced in the brain can influ- ence neurons by modulating membrane-bound receptors (including gamma-aminobutyric acid type A [GABAA] and glutamate receptors) and subsequently influencing neuronal excitotoxicity and apoptosis (reviewed in Leskiewicz et al., 2006). Progesterone may also promote myelin repair (Chesik and De Keyser, 2010; Labombarda et al., 2009). Potential neuroprotective mechanisms have been reviewed in the context of TBI by Stein (2008). Although no published work has directly tested the hypothesis that vitamin D supple- mentation improves resilience to TBI in otherwise vitamin D–adequate animals, an examina- tion of data collected using other models of brain injury suggests the need for more work in this area. For example, eight days of treatment with 1,25 dihydroxyvitamin-D3 reduced tissue damage in the rat brain subjected to the middle cerebral artery occlusion model of stroke (Wang et al., 2000). Interestingly, four days of vitamin D treatment were ineffective, suggesting a dose-response curve that needs to be examined. EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies There have been no clinical trials to assess the efficacy of vitamin D as a treatment for TBI or for other related diseases or conditions included in the review of the literature (sub- arachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy). Animal Studies No published studies have used vitamin D supplementation to treat TBI. In vitro work, however, has shown that vitamin D has direct neuroprotective and antiapoptotic functions, and protects cultured cortical neurons against excitotoxic damage (Kajta et al., 2009). The

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231 VITAMIN D same report further showed that administration of a single dose of 1,25 dihydroxyvitamin D3 (2 μg/kg) 30 minutes after hypoxia-ischemia in seven-day-old rats effectively reduced brain damage in these animals (Kajta et al., 2009). Although clearly very different from the accepted models of TBI, these data do suggest that future studies to examine the possible effectiveness of vitamin D in TBI models are warranted. CONCLUSIONS AND RECOMMENDATIONS An examination of the literature on the possible role of vitamin D in improving re- silience to TBI and in the treatment of TBI has identified a number of unanswered ques- tions that reveal gaps in our current knowledge. It is not known whether chronic vitamin D supplementation alone improves resilience. There also is no clear evidence yet to show the extent to which vitamin D supplementation is effective in treating TBI, the therapeutic window for treatment after TBI, or the optimal dose. Although it appears that adequate vitamin D status is necessary to the action of effective treatments such as progesterone, it is not currently known if vitamin D supplementation that exceeds recommended doses would improve progesterone efficacy or enhance other treatments. It is, however, recommended that military personnel ensure adequate intakes to meet the RDA for vitamin D. Because the current vitamin D status of military personnel is not definitive, the committee recommends in Chapter 5 that dietary assessments be conducted across military settings. A retrospective assessment of pre- and postinjury nutrition status is likewise recommended in Chapter 5. This should include investigating serum vitamin D levels in patients during the acute phase of TBI, with a range of severity from mild/concussion to severe injuries, to explore whether preinjury vitamin D levels are associated with different outcomes. Progesterone was not included for independent evaluation in this report because, al- though it is incorporated in some dietary supplements, there was no evidence that these preparations will have positive effects on TBI. Although progesterone can be taken orally in a micronized form that enhances solubility in aqueous solutions and absorption in the gastrointestinal tract (Fitzpatrick and Good, 1999), it appears that its positive effects in TBI are achieved only via intravenous administration and at therapeutic doses (Wright et al., 2005, 2007; Xiao et al., 2008). Although some phytoprogestins have been identified by their ability to bind progesterone receptors on the breast carcinoma cell line T47D (Zava et al., 1998), none of the herbal extracts that bound the receptors were agonists. They were either neutral or were progestin antagonists (examples include red clover, licorice, and nutmeg). Altogether, there is no evidence that oral administration of progesterone or phytoprogestins will provide a benefit as treatment for TBI. RECOMMENDATION 15-1. The committee recommends more animal studies be conducted to determine if vitamin D enhances the beneficial actions of progesterone in the treatment of TBI. If this synergistic effect is confirmed in animals, then studies in humans should be conducted to evaluate the extent to which vitamin D supplementation might improve the efficacy of progesterone treatment. RECOMMENDATION 15-2. Based on animal studies showing a requirement of vita- min D for the efficacy of progesterone therapy, future animal studies are recommended to test the efficacy of using vitamin D supplements to improve resilience to TBI. Should the data from animal studies support use of this steroid hormone, human trials should be implemented to test the efficacy of vitamin D in populations at high risk for TBI.

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