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Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington (DC): National Academies Press (US); 2011.

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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

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7Antioxidants

Oxidative stress has been implicated as a central pathogenic mechanism in traumatic brain injury (TBI) because the brain is especially vulnerable to such stress, compared to other tissues (Floyd, 1999; Floyd and Carney, 1992). Overproduction of reactive oxygen species (ROS), that is, chemically reactive molecules containing oxygen, can trigger many of the harmful biological events associated with TBI such as DNA (deoxyribonucleic acid) damage, brain-derived neurotrophic factor (BDNF) dysfunction, and disruption of the membrane phospholipid architecture, and has therefore been suggested as a principal culprit in both acute and long-term events of TBI (Eghwrudjakpor and Allison, 2010; Hall et al., 2010). The effects of antioxidants on TBI have not yet been examined in human studies; however, several clinical trials have investigated whether antioxidant supplementation could reduce the risk of developing other forms of trauma (e.g., stroke and epilepsy) or protect against developing adverse health outcomes after injury. This chapter offers the current evidence to support further exploration of the role of antioxidants as neuroprotectants for TBI.

There are many compounds having antioxidant properties, some of which are essential nutrients. As evidence became available, it was observed that effectiveness in animals or excellent antioxidant activity observed in vitro does not necessarily translate into effectiveness to prevent human diseases associated with oxidative stress. Initial expectations of these compounds to prevent chronic diseases associated with oxidative stress have been disappointed. It has nevertheless become clear that oxidative stress after TBI triggers many of its outcomes, and antioxidant compounds should be considered to ameliorate these outcomes. It would not be feasible for this committee to do a review of all the many compounds that have been identified as having antioxidant activity. Vitamins E and C were selected as examples of antioxidant nutrients for this review because their potential to prevent chronic diseases has been studied extensively. Some non-essential food components with reported antioxidant properties also are reviewed in this chapter. Finally, based on the fact that antioxidants seem to act synergistically, the possibility that a combination of antioxidants might be more effective that a single one is also considered. The intention of this chapter is not to review every combination of antioxidants that might have been tested, but to give a flavor of the potential benefits of this class of compounds when used in combination.

VITAMIN E (ALPHA-TOCOPHEROL)

Introduction

Vitamin E is a family of fat-soluble α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. The α-tocopherol has been the most studied, as it is the form preferentially absorbed and transported to tissues in humans. For example, the U.S. dietary requirements have been developed considering mainly this form. Although vitamin E is an antioxidant that stops the production of ROS formed when fat undergoes oxidation, its in vivo roles are not well understood. The level of alpha-tocopherol is high in the brain, and its concentration is normally regulated (Spector and Johanson, 2007).

The consumption of vitamin E beyond the requirement levels cited in the Dietary Reference Intakes (DRIs) has been studied extensively from 1990 through 2010. Early observational studies and animal studies suggested that vitamin E’s antioxidant properties would protect the body against devastating chronic diseases having oxidative stress as part of their pathobiology, such as cardiovascular diseases and cancer; however, results from observational studies are mixed, and have not resulted in a clear association between intake of vitamin E and reduction of chronic disease (Hirvonen et al., 2000; Mezzetti et al., 2001; Watkins et al., 2000; Yochum et al., 2000). Large human trials conducted since 2000 have also failed to demonstrate such benefits. The reader is referred to the numerous discussions that can be found on this topic and on the potential reasons for the disappointing findings (Fletcher and Fairfield, 2002; Huang et al., 2006; Lichtenstein, 2009; Pryor, 2000; Steinberg, 2000). Table 7-1 lists large human trials that have evaluated the association of vitamin E with cardiovascular diseases, as well as a recent study on TBI presented at a conference (Razmkon et al., 2010). The occurrence or absence of adverse effects in humans is included if reported by the authors. The 2006 IOM report Nutrient Composition of Rations for Shortterm, High-Intensity Combat Operations reviewed vitamin E in the context of preventing oxidative damage from exhausting physical exercise in the military. That report showed no clear benefit either in reducing muscle injury due to exercise or in improving performance, and therefore no recommendation was offered to increase intake of vitamin E (IOM, 2006). That report did not review evidence on vitamin E and potential benefits for TBI.

TABLE 7-1. Relevant Data Identified for Vitamin E (alpha-tocopherol, alpha-tocotrienol).

TABLE 7-1

Relevant Data Identified for Vitamin E (alpha-tocopherol, alpha-tocotrienol).

Uses and Safety

The Recommended Dietary Allowance (RDA) for vitamin E (as alpha-tocopherol) is set at 15 mg for men 19–50 years of age. This requirement was based on maintaining plasma tocopherol concentration at a level that limited hemolysis in red blood cells resulting from peroxide exposure to less than 12 percent.

A comparison of U.S. dietary intake from National Health and Nutrition Examination Survey (NHANES) 2001–2002 data with the Estimated Average Requirements (EARs) of alpha-tocopherol (see Table 5-2 in Chapter 5) suggests that 89 percent of males and 97 percent of females older than 19 years of age consume far less vitamin E than the recommended EAR. However, overt signs of vitamin E deficiency occur very rarely in humans and have not been reported as a result of low dietary intakes, except in conjunction with moderate to severe malnutrition.

The Tolerable Upper Intake Level (UL) of vitamin E was established at 1,000 mg, based on hemorrhagic effects. However, there are concerns about increasing mortality if doses larger than 400 IU (400 mg of all-rac-alpha-tocopheryl acetate) are given (Miller et al., 2005). Although the data are mixed, a 2007 review of the adverse-event data for high doses of vitamin E revealed that those papers categorized as having high methodological quality were more likely to report increased mortality than studies with low methodological quality (Bjelakovic et al., 2007).

Evidence Indicating Effect on Resilience

Human Studies

Except for one recent study reported at a conference, there has been no human study conducted to test the potential effects of vitamin E on providing resilience to TBI. Some additional indication of this possibility comes from data on vitamin E and cardiovascular diseases, where vitamin E was shown to decrease oxidation of low-density lipoproteins. For risk of cardiovascular diseases, this chapter presents only the larger randomized controlled studies on vitamin E.

Contrary to preliminary studies, results from clinical trials do not support a protective effect of vitamin E supplementation on the risk of cardiovascular diseases (CVD) (Eidelman et al., 2004; Lichtenstein, 2009; Steinberg, 2000). In a double-blind clinical trial including 1,434 individuals aged 55 years or older with both Type 2 diabetes and the haptoglobin 2-2 genotype (which is associated with a high level of oxidative stress), participants were randomized to vitamin E (400 IU/day) or placebo (Milman et al., 2008). After 18 months of follow-up, vitamin E treatment was not significantly associated with a lower incidence of stroke than the placebo. In another randomized, placebo-controlled trial including 9,541 adults (aged 55 or older) with CVD or diabetes in addition to one other risk factor of CVD, treatment with vitamin E (400 IU/day) for an average 4.5 years did not significantly decrease the risk of major cardiovascular events (occurrence of myocardial infarction [MI], stroke, or cardiovascular death) or stroke, compared with the placebo group (Yusuf et al., 2000). Vitamin E supplementation similarly failed to show protective effects against the risk of stroke in the Women’s Health study (n = 39,873, 600 IU/day of vitamin E for 10 years) (Buring, 2006; Lee et al., 2005), the Women’s Antioxidant Cardiovascular study (n = 8,171, 600 IU/day of vitamin E every other day for 9.4 years) (Cook et al., 2007), and the Physicians’ Health study-II (n = 14,641, 400 IU/day of vitamin E every other day for 8 years) (Sesso et al., 2008). A trial including 28,519 male cigarette smokers who were free of stroke at baseline found that vitamin E supplementation (50 mg/day) for approximately six years significantly increased the risk of developing fatal hemorrhagic strokes, but prevented cerebral infarction (Leppala et al., 2000).

In a 2010 meta-analysis including nine randomized controlled trials, vitamin E supplementation was not associated with total stroke. However, when stroke subtypes were analyzed, use of vitamin E increased risk for hemorrhagic stroke but decreased risk for ischemic stroke, which is much more common in the United States (Schürks et al., 2010).

Animal Studies

Three animal studies on the effects of vitamin E on TBI were identified. In a 2010 study (Wu et al., 2010), male rats (weighing 200–240 g) were fed a regular diet with or without α-tocopherol (500 IU/kg) for four weeks (n = 6–8 within each group) prior to administration of a mild fluid percussion injury (FPI). When assessed one week after brain injury, vitamin E supplementation was associated with a favorable brain status of oxidized proteins, brain-derived neurotrophic factor (BDNF), calcium/calmodulin dependent kinase II (CaMKII), synapsin I, cAMP-response element-binding protein, superoxide dismutase, and Sir2. Rats treated with vitamin E also had better cognitive function, as assessed by a Morris water maze (MWM) test starting at day 5 after TBI, than untreated rats. Protective effects of vitamin E on cognitive impairment due to TBI were further supported by another study using Tg2576 mice (female, aged 11 months), a mouse model of Alzheimer’s disease (AD) brain amyloidosis. Conte and colleagues (2004) found that mice with preinjury supplementation of vitamin E (2 IU/g, n = 9) had a significant decrease in brain lipid peroxidation levels and a better cognitive performance in the MWM test compared with untreated mice (n = 13), although the two groups had similar levels of amyloid deposition. In another animal study including 65 guinea pigs (aged 3–4 months), alpha-tocopherol (100 mg/kg) administered intraperitoneally before brain injury was also associated with lower lipid peroxide levels in traumatized brain tissues, independent of severity of injury (Inci et al., 1998).

Evidence Indicating Effect on Treatment

Human Studies

There has been no human study conducted to test the potential effectiveness of vitamin E for treating TBI. Clinical trials examining whether vitamin E exerts neuroprotective effects among participants with various other forms of brain trauma have generated mixed results. Raju and colleagues (1994) conducted a double-blind, crossover trial of vitamin E among 43 patients with uncontrolled epilepsy, and observed no significant difference in seizure frequency between the group receiving vitamin E and the placebo group. Another small trial including 30 patients with acute ischemic stroke found that vitamin E supplementation had no significant effect on early neurological outcomes or on the level of plasma lipid peroxides after acute ischemic stroke, but it led to a significant improvement in subsequent recovery and rehabilitation (Daga et al., 1997). In a trial (n = 11,324 patients in the GISSI-Prevenzione trial) including 72 ischemic stroke patients, the use of antioxidants (300 mg of α-tocopherol daily) was not associated with a lower risk of mortality, but after a year of follow-up there was a trend to lower mortality in those groups treated with polyunsaturated fatty acids (850–882 mg eicosapentaenoic or docosahexaenoic acid [EPA/DHA] [ratio EPA/ DHA 1:2] daily, either alone or in conjunction with 300 mg of α-tocopherol) (Garbagnati et al., 2009; GISSI-Prevenzione Investigators, 1999). Recently, a small (100 patients, 83 male), randomized, clinical controlled study showed that in patients with TBI (Glasgow Coma Scale scores of 8 or less and radiologic diagnoses of diffuse axonal injury), in-hospital mortality was significantly lower in those receiving high doses of vitamin E (intravenous at 400 IU daily for 7 days) than in those receiving low (500 mg daily for 7 days) or high (10 g on the day of admission and 4 days later) doses of vitamin C or placebo (Razmkon et al., 2010).

VITAMIN C (ASCORBIC ACID)

Introduction

Vitamin C (L-ascorbic acid or L-ascorbate) is an essential nutrient that protects the body against oxidative stress. The biological function of vitamin C comes from its ability to donate reducing equivalents to reactions, including reduction of reactive oxygen that damages cells. It is a cofactor in at least eight enzymatic reactions, and is required for metabolic reactions. Vitamin C is the electron donor for eight enzymes involved in collagen hydroxylation, carnitine biosynthesis, and hormone and amino acid biosynthesis. Vitamin C deficiency is characterized by impairments in connective tissue, specifically impairment of collagen synthesis. Vitamin C has also been shown to affect components of the immune response (IOM, 2000). The IOM considered levels higher than the Military Dietary Reference Intakes (MDRIs) for prevention of oxidative damage and muscle injury associated with high-intensity exercise (IOM, 2006) or for acute oxidative stress (IOM, 1999), but found insufficient evidence to make such recommendations. Those reports did not review evidence on vitamin C and potential benefits for TBI.

The brain has particularly high levels of vitamin C, approximately 100 times higher than levels in most other tissues in the body (Grunewald, 1993; Rice, 2000). Vitamin C is pumped into the central nervous system by the sodium-dependent vitamin C transporter-2 systems in series in the epithelial and neuronal cell membranes, but there is no sound evidence for a carrier-mediated transport (Spector, 2009). A study to assess antioxidant depletion in patients additionally showed that those with intracranial hemorrhage and head trauma had lower plasma levels of vitamin C than controls, and that its levels were significantly inversely correlated with the several outcomes of the disease (i.e., severity of the neurological impairment and diameter of the lesion). However, to the committee’s best knowledge, there are no human or animal studies to examine the potential neuroprotective effects of vitamin C on TBI, except for the study by Razmkon described above presented at a 2010 conference. The committee identified five human studies regarding vitamin C supplementation and stroke or subarachnoid hemorrhage. Table 7-2 lists those studies, plus the study on TBI presented at a conference. As with Table 7-1, the occurrence or absence of adverse effects is included if reported.

TABLE 7-2. Relevant Data Identified for Vitamin C.

TABLE 7-2

Relevant Data Identified for Vitamin C.

Uses and Safety

The EAR for vitamin C was based on maintaining near-maximal neutrophil concentrations with minimal urinary loss, and was set at 75 mg/day for men and 60 mg for women. A comparison of U.S. dietary intake from NHANES 2001–2002 data with the EAR of vitamin C (Table 5-2) suggests that 40 percent of males and 38 percent of females older than 19 years of age consume less vitamin C than the recommended EAR. The UL for vitamin C is 2 g/day based on gastrointestinal disturbance, but there are concerns that vitamin C could act as a prooxidant, depending on the dose (Childs et al., 2001).

Evidence Indicating Effect on Resilience

Human Studies

Effects of vitamin C supplementation on risk of stroke were examined in the Women’s Antioxidant Cardiovascular Study (n = 8,171, 500 mg/day for 9.4 years) (Cook et al., 2007) and the Physicians’ Health Study II (n = 14,641, 500 mg/day for 8 years) (Sesso et al., 2008). No protective effects were observed in these trials, either for total, or for different subtypes of stroke (Cook et al., 2007; Sesso et al., 2008).

Evidence Indicating Effect on Treatment

Human Studies

Polidori and colleagues (2005) reported that treatment with vitamin C (200 mg/day) in combination with aspirin therapy in 59 patients with ischemic stroke of recent onset (< 24 hours) was associated with significantly lower lipid peroxidation, as assessed by plasma 8,12-iPF2α-VI concentrations, than a control group receiving only aspirin. Kodama and colleagues (2000) also showed that subarachnoid hemorrhage patients (n = 217) who were treated with urokinase and vitamin C recovered without neurological deficits. (It should be noted, however, that this study lacked a control group.) In another trial including 46 ischemic stroke patients, 1,000 mg/day of vitamin C had no impact on motor recovery (Rabadi and Kristal, 2007).

The small randomized, clinical controlled study described above that showed benefits associated with high doses of vitamin E following TBI did not find vitamin C to be associated with positive neurologic outcomes, but the high doses of the vitamin (10 g on the day of admission and 4 days later) slowed the progression of perilesional edema (Razmkon et al., 2010).

COMBINATION OF ANTIOXIDANTS

Evidence Indicating Effect on Resilience

Human Studies

Results from observational studies are mixed and have not resulted in any clear association between chronic diseases and intake of antioxidants (Hirvonen et al., 2000; Mezzetti et al., 2001; Voko et al., 2003; Watkins et al., 2000; Yochum et al., 2000). Although the committee’s literature reviews did not include cancer as a disease outcome because its pathology and etiology is dissimilar to that of TBI, one study is presented here to illustrate how a combination of antioxidants showed benefits where single nutrients did not. A randomized controlled trial was conducted in a region of China where esophageal and gastric cancers are prevalent and low intake of micronutrients has also been observed. Mortality and cancer incidence were ascertained for 29,584 adults who were assigned to take daily vitamin and mineral supplementation of (1) retinol and zinc; (2) riboflavin and niacin; (3) vitamin C and molybdenum; and (4) beta-carotene, vitamin E, and selenium. Those in the group taking beta-carotene, vitamin E, and selenium had lower mortality than controls, mainly because of lower cancer rates (Blot et al., 1993).

There are other studies showing that supplementation with both vitamin C and vitamin E (compared to vitamins C or E alone) is more effective in protecting from oxidative stress because vitamin E is regenerated by vitamin C. There were 8,171 women recruited for the Women’s Antioxidant Cardiovascular Study, designed to test the effects of ascorbic acid (500 mg/day), vitamin E (600 IU every other day), and beta-carotene (50 mg every other day) on cardiovascular disease in a 2 × 2 × 2 factorial design. Participants were 40 years of age or older, postmenopausal or had no intention of becoming pregnant, and had a self-reported history of CVD or at least three cardiac risk factors (Cook et al., 2007). During 9.4 years of follow-up, those in the active groups for both vitamin E and ascorbic acid had a lower risk of developing stroke relative to those in the placebo group for both agents. However, other two- or three-way interactions among these three antioxidants were not significant for stroke (Cook et al., 2007). In contrast, the Physicians’ Health Study II Randomized Controlled Trial, a 2 × 2 factorial design to test the effect of ascorbic acid (500 mg/day) and vitamin E (400 IU every other day) in 14,641 U.S. men aged 50 years or older, failed to find any significant protective effects of these agents or their combination on stroke risk during a mean follow-up of eight years (Sesso et al., 2008). Another large, randomized controlled study that observed vascular disease, cancer, and other adverse outcomes in which participants (20,536 adults aged 40–80) were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo showed no significant effects on cancer incidence or on hospitalization for any other nonvascular cause (Heart Protection Study Collaborative, 2002).

In another randomized controlled trial in Finland that included 28,519 male cigarette smokers free of stroke at baseline, the incidence of stroke in those who received both activated vitamin E (50 mg/day) and beta-carotene (20 mg/day) (258 out of 7118) was similar, during mean six years of follow-up, to the incidence in those who received placebos (252 out of 7153). However, the significance of difference of stroke risk between these two groups was not reported (Leppala et al., 2000).

Evidence Indicating Effect on Treatment

Human Studies

In a randomized, double-blind and placebo-controlled trial, 200 patients in intensive care (113 with organ failure after complicated cardiac surgery, 66 with major trauma, and 21 with subarachnoid hemorrhage) were provided intravenous antioxidant supplements (vitamin C, vitamin E, selenium, zinc, and vitamin B1) for 5 days, starting within 24 hours of admission. There was a reduction of early organ dysfunction and significantly reduced serum C-reactive protein concentrations relative to the control group (Berger et al., 2008). The difference did not, however, reach a significant level in individual subgroups (e.g., trauma patients or patients with subarachnoid hemorrhage) (Berger et al., 2008). A study including 96 acute ischemic stroke patients found that use of antioxidants (800 IU vitamin E and 500 mg vitamin C) within 12 hours of symptom onset enhanced antioxidant capacity, mitigated oxidative damage, and may have had an anti-inflammatory effect, as assessed by serum C-reactive protein concentrations (Ullegaddi et al., 2006).

There has been one ongoing clinical trial identified that will contribute to the strength of the evidence about whether antioxidants may be beneficial in improving outcomes of TBI. The trial will examine whether providing high doses of glutamine and antioxidants (i.e., selenium, zinc, beta carotene, vitamin E and vitamin C) to critically ill patients will be associated with improved survival. Although patients with severe acquired brain injury are excluded from the study, the critically ill might also experience other less severe brain injuries; hence, the results of this study will contribute to our knowledge about this potential combination of antioxidants.

CONCLUSIONS AND RECOMMENDATIONS

The use of single antioxidant supplements to treat a variety of chronic diseases, including coronary heart disease, cancer, and ocular and skin diseases, has been disappointing. These apparently conflicting results may be due to the fact that all the trials with individual antioxidants reported here were conducted with α-tocopherol. The interactions of a diet high in α-tocopherol with other forms of vitamin E (e.g., γ-tocopherol, the form most abundant in the American diet) are not known. Other reasons for this discrepancy are possible, such as interactions with other food components and the existence of confounders such as diet and lifestyle patterns. For example, individuals who report using nutrient supplements are also more likely to have overall more healthful lifestyles. In the context of TBI, several conclusions can be derived from the review of the evidence of potential benefits of specific antioxidants. Although oxidative stress is a substantial risk factor for adverse events following TBI, there is minimal evidence at this time to support recommendations to either supplement the diet with these nutrients beyond the dietary requirements or provide them after injury. For example, while the results from animal trials with vitamin E are encouraging, the human trials do not support the concept that vitamin E could have beneficial effects for TBI. There is one recent study with encouraging results for treating TBI patients with vitamin E. However, the committee concluded that, as with the study on cancer, a combination of various antioxidants including vitamins E, C, and carotenoids might be more efficacious. There is sufficient literature from animal and human trials with other acute injuries associated with oxidative stress to warrant a carefully designed trial with TBI patients using an array of antioxidants. Any trials that may be undertaken should ensure that dose levels of antioxidants do not approach levels that might cause adverse events, such as higher risk of mortality (Miller et al., 2005). The committee recommends that DoD track the findings of the current trial using a combination of antioxidants in the critically ill and any similar future human trials that may follow.

RECOMMENDATION 7-1. Based on the literature from animal and human trials concerning stroke and epilepsy, DoD should consider a clinical trial with TBI patients using an array of antioxidants in combination (e.g., vitamins E and C, selenium, beta-carotene).

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Bookshelf ID: NBK209332

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