7
Antioxidants

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



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7 Antioxidants 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 effective- ness to prevent human diseases associated with oxidative stress. Initial expectations of these compounds to prevent chronic diseases associated with oxidative stress have been disap- pointed. 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 ex- amples 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 anti- oxidants 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 88

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89 ANTIOXIDANTS 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-, b-, 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 Short- term, 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. 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 per- cent 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

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90 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-1 Relevant Data Identified for Vitamin E (alpha-tocopherol, alpha-tocotrienol) Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Razmkon TBI (Glasgow Multi-center, Postinjury, Vitamin E significantly decreased in- et al., 2010 Coma Scale randomized, vitamin E hospital mortality following TBI by 8% scores of 8 double-blind, (intravenous at (p=0.01). or less and placebo- 400 IU/day for The vitamin E group had significantly radiologic controlled 7 days) better Glasgow Outcome Scale scores diagnoses of trial, Postinjury, at discharge and at 2 and 6 months of diffuse axonal na=100 (83 vitamin C (500 follow up (p=0.04). injury) male) mg/day for No adverse effects were observed. seven days or 10 g on the day of admission and 4 days later), or placebo Schürks Stroke Meta- Vitamin E Vitamin E supplementation did not et al., 2010 analysis of 9 supplementation reduce the risk for total stroke, but it randomized, was associated with increased risk for hemorrhagic stroke (pooled RRb=1.22; controlled 95% CIc: 1.00, 1.48, p=0.045). And trials vitamin E was associated with decreased risk for ischemic stroke (pooled RR=0.90; 95% CI: 0.82, 0.99, p < 0.02). There was no evidence of heterogeneity (I2d=0.0%) or small study effect for either variable. Data on adverse bleeding from vitamin E treatment is unclear: fatal bleeding among two individuals in the treatment group was reported in one trial, while another trial reported non-fatal bleedings among both the treatment and placebo groups. A third trial found no overall increased rate of bleeding, but observed a small significantly increased risk for epistaxis among the treatment group. Milman Cardiovascular Randomized, Vitamin E (400 Analysis of composite cardiovascular et al., 2008 events (i.e, prospective, IU/day) or disease events (CVD death, non-fatal MI, myocardial double-blind placebo and stroke) show that subjects in vitamin infarction trial E group had significantly fewer events [MI], stroke, or than control group (2.2% in vitamin E n=1,434 DM vs. 4.7% in placebo; HRe=0.47, 95% CI: cardiovascular individuals death) in patients 0.27–0.82; p=0.01 by Log-Rank). This aged 55 years with type 2 significance can largely be attributed or older diabetes mellitus to vitamin E treatment effect on MI with Hp 2-2 (DM) (1.0% in vitamin E vs. 2.4% in placebo; genotype p=0.04). Perceived side effects caused 11 individuals (5 in vitamin E group and 6 in placebo group) to discontinue their participation in the study.

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91 ANTIOXIDANTS TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Sesso et al., Cardiovascular Randomized, Vitamin The cumulative incidence rate of major 2008 events (MI, double-blind, E (400 IU cardiovascular events per year for α-tocopherol) stroke, or CVD placebo- vitamin E and placebo were similar. death) controlled trial or placebo every Vitamin E also had no effect on the (Physicians’ other day for incidence of MI, stroke, or congestive Health Study mean 8 years heart failure. However, among the men II) who were diagnosed with stroke during n=14,641 the study period, risk of hemorrhagic U.S. male stroke was significantly higher in those physicians, in vitamin E group, compared to placebo aged 50 years group (HR=1.74, 95% CI: 1.04–2.91; or older p=0.04). Vitamin E also had no preventive effect on non-fatal cardiovascular events, CVD mortality, or total mortality. No interaction with vitamin C was found for any of the cardiovascular events. Compared to placebo, vitamin E had no significant adverse effects. Cook et al., Cardiovascular Randomized, Vitamin E After excluding noncompliant subjects (600 IU d-α- 2007 events (MI, double-blind, from analysis, vitamin E had significant stroke, coronary placebo- tocopherol effect reducing overall CVD morbidity revascularization, controlled acetate) every and mortality (RR=0.87, 95% CI: 0.76– or CVD death) trial (Women’s other day 0.99; p=0.04), stroke (RR=0.73, 95% Antioxidant CI: 0.54–0.98; p=0.04), and combination Cardiovascular MI, stroke, and CVD death (RR=0.77, Study) 95% CI: 0.64–0.92; p=0.005). And in those with previous CVD events n=8,171 at baseline, fewer CVD events were female health observed during the study period in the professionals, vitamin E group (RR=0.89, 95% CI: aged 40 years 0.79–1.00; p=0.04). or older; mean follow-up Subjects taking both vitamins C and years=9.4 E had significantly fewer strokes than those taking placebos for both vitamins (RR=0.69, 95% CI: 0.49–0.98; p=0.04), suggesting an interaction (p for interaction=0.02). No statistically significant adverse effects were observed. continued

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92 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Buring, Cardiovascular Randomized, Aspirin (100 Vitamin E had no significant effect on 2006a events (MI, placebo- mg) or placebo major CVD events, total stroke, all stroke, or CVD controlled vs. vitamin E stroke subtypes, total MI, all MI events, Lee et al., death) and trial (Women’s (600 IU) or or all-cause death. But vitamin E did 2005 cancer Health Study) placebo every reduce CVD death by 24% (RR=0.76, other day p=0.03). n=39,876 In women > 65 years old, vitamin E female health professionals reduced total CVD events (RR=0.74, p=0.009), MI (RR=0.66, p=0.04), and CVD death (RR=0.51, p < 0.001). Vitamin E had no effect at all on cancer. The only significant adverse effect of vitamin E was 6% increased risk of epistaxis (RR=1.06, p=0.02). No interaction between aspirin and vitamin E was noted. Eidelman Cardiovascular Meta- Natural and Meta-analysis of the 7 trials showed et al., 2004 events (MI, analysis and synthetic that compared to placebo, vitamin stroke, or CVD overview of 7 vitamin E, E treatment was not significant in death) randomized 30–800 mg preventing CVD events. 4,832 major trials from CVD events occurred in patients 1990 to receiving vitamin E treatment, and present on 4,895 events occurred in placebo-treated patients (ORf=0.98, 95% CI: 0.94–1.03). effectiveness of vitamin E in Vitamin E also had no effect on CVD the treatment death (OR=1.00, 95% CI: 0.94–1.05), and prevention non-fatal MI (OR=1.00, 95% CI: of CVD 0.92–1.00), non-fatal stroke (OR=1.03, total 95% CI: 0.93–1.14), ischemic stroke n=106,625 (OR=1.01; 95% CI: 0.90–1.14), or hemorrhagic stroke (OR=1.24, 95% CI: 0.96–1.59). No adverse effects were mentioned.

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93 ANTIOXIDANTS TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Heart Cardiovascular Randomized, Antioxidant Compliance to treatment was high and Protection events (MI, placebo- vitamin equal in both groups (83% for both). Study stroke, or CVD controlled supplementation Analysis of blood assays showed that Collaborative death) trial (Heart (600 mg subjects taking vitamins had higher levels Group, 2002 Protection [synthetic] of plasma α-tocopherol, vitamin C, and Study) vitamin E, 250 b-carotene. mg vitamin n=20,536 UK C, and 20 mg Vitamins had no effect on mortality due adults, aged b-carotene), to composite CVD events, any CVD 40–80 years daily, mean 5-yr subevents, or any non-CVD events. at high risk follow up for coronary No significant effects were noted for disease due vitamins in incidence of: stroke, of all to previous types and severity; any major CVD medical events, regardless of whether subjects history had CVD in the past or not; cancers; neuropsychiatric disorders; respiratory diseases; or fractures. Vitamin treatment group had increase of 0.15 mmol of total cholesterol, 0.08 mmol of low-density lipoprotein cholesterol, and 0.21 mmol of triglycerides (p < 0.05 for all). Over 5 years of vitamin use, the incidence of major adverse events (e.g., heart attacks, strokes, cancers) did not substantially increase. Collaborative Cardiovascular Randomized, 2X2 factorial Vitamin E had no significant effect Group of events (MI, placebo- design: vitamin on combined endpoints (CVD death, the Primary stroke, or CVD controlled, E (100 mg non-fatal MI, and non-fatal stroke) or Prevention death) open-label synthetic most individual events (CVD and non- α-tocopherol) Project, 2001 trial (Primary CVD death, all MI, all stroke, angina Prevention daily and pectoris, transient ischemic attack, and Project) aspirin (100 mg revascularization). enteric-coated n=4,495 aged Vitamin E significantly reduced risk of aspirin a day) 50 years or peripheral-artery disease (RR=0.54, 95% for mean 3.6 older, with CI: 0.30–0.99; p=0.043). years at least one No significant adverse effect was of the major observed for vitamin E. recognized cardiovascular risk factors continued

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94 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Leppala Stroke Randomized, 2X2 factorial Compared to those taking only b-carotene or placebo, subjects taking et al., 2000 double-blind, design: 50 mg α-tocopherol or α-tocopherol had a non-significantly placebo- controlled placebo daily; higher incidence of subarachnoid trial (Alpha- and 20 mg hemorrhage and a significantly lower b-carotene or Tocopherol, incidence of cerebral infarction Beta-Carotene placebo daily (RR=0.86, 95% CI: 0.75–0.99; p=0.03). Cancer for 6 years α-tocopherol had no effect on incidence Prevention of intracranial hemorrhage or total Study [ATBC stroke. Study]) There was no interaction between n=28,519 α-tocopherol and b-carotene. Finnish, male, cigarette No adverse effects were mentioned. smokers aged 50 to 69 years without history of stroke Yusuf et al., Cardiovascular Randomized, Natural vitamin Other than a 17% increase in risk 2000 events (MI, placebo- E (400 IU/day) of heart failure (RR=1.17, 95% CI: stroke, or CVD controlled trial or matching 1.03–1.32, p=0.02), vitamin E had no death) placebo plus effect on total CVD incidence, total CVD n=9,541, aged either an death, MI, stroke, all-cause mortality 55 years or angiotensin- rate, hospitalization for unstable angina older at high converting- or heart failure, revascularization or limb risk because enzyme amputation, new onset or worsening they had CVD inhibitor angina, or diabetes complications. There or diabetes in (ramipril) was still no effect after stratification by addition to or matching age, sex, history of CVD and diabetes, one other risk placebo and smoking. factor No interaction between vitamin E and average ramipril was noted. follow-up period=4.5 No significant adverse effects of vitamin years E were observed.

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95 ANTIOXIDANTS TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Daga et al., Acute ischemic Randomized, Vitamin E At day 15, vitamin E group had plasma 1997 stroke placebo- (300 mg/day) lipid peroxidation level that was 1.67 controlled trial or placebo; mmol/mL lower than the placebo group (p < 0.01). Plasma α-tocopherol level in patients n=50 evaluated at day the vitamin E group was 4.52 mmol/mL 1, day 15, and 6 higher than that of the placebo group (p < 0.01). There was no difference between weeks the two groups regarding plasma b-carotene level. Neurological condition was measured using Matthew scale from days 1–15 and Barthel Index (BI) from day 15–6 weeks. Neither group experienced change in their Matthew scale between day 1 and day 15; there was also no significant difference between groups. However, vitamin E group achieved greater improvement at 6 weeks with an increase of 246 points on their BI (p < 0.05); the placebo group had an increase of 136.8 points. No adverse effects were mentioned. d-α-tocopherol Raju et al., Refractory Randomized, Compared to baseline, all patients 1994 epilepsy double-blind, (600 IU/day) had a significant reduction in seizure frequency (p < 0.001) with no significant placebo- or placebo as controlled, add-on therapy difference between the vitamin E arm cross-over trial to antiepileptic and the placebo arm. In those who had > 50% reduction, vitamin E also had no drugs n=43 effect. Patients with primary generalized seizures had significantly reduced seizure frequency during treatment period compared to baseline (p < 0.05) but the reduction achieved during the vitamin E arm was similar to the placebo arm. In all patients, order of vitamin E treatment made no difference (p > 0.1). No significant side effects were observed for vitamin E. Tier 2: Observational studies None found continued

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96 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Tier 3: Animal studies Wu et al., Mild TBI Male Sprague- Preinjury, Compared to injured rats on regular diet, 2010 (mTBI), mild Dawley rats regular diet injured rats on supplemented diet had fluid percussion (containing better performance in the Morris water maze (p < 0.05). injury 40 IU/kg of vitamin E) or Level of oxidative stress in injured rats supplemented was 39% higher than that of sham- diet (with 500 injured rats (p < 0.01), but vitamin E IU/kg of vitamin supplementation decreased the level E) beginning 4 of oxidative stress to 44% of the level weeks prior to observed in sham-injured rats (p < 0.01 injury vs. injured, regular diet rats and sham rats). Vitamin E supplementation significantly restored levels of brain-derived neurotrophic factors after injury. Compared to rats on regular diet, rats on vitamin E supplemented diet had higher levels of synapsin I (p < 0.05) and CREB (p < 0.05). Vitamin E also restored the level of CaMKII to 96% of the sham-injured rats, the level of superoxide dismutase to 92% of sham-injured rats, and the level of Sir2 to 95% of sham-injured rats. Conte et al., Repetitive Tg2576 female Preinjury: Vitamin E supplementation increased the level of brain vitamin E (p < 0.01) and 2004 concussive brain mice regular injury (RCBI, diet or diet decreased the level of 8,12-iso-iPF2α-VI (p < 0.01) in injured mice. There was two injuries, supplemented 24 hours apart) with 2 IU/g of no difference in brain vitamin E level and modified vitamin E 4 between sham-injured and untreated controlled weeks before mice, but untreated, injure mice had cortical impact injury significantly higher level of 8,12-iso- model iPF2α-VI compared to sham-injured mice Postinjury: (p < 0.05). regular diet or diet Mice on vitamin E supplemented diet supplemented had improved cognitive function than mice on regular diet (p < 0.01). with 2 IU/g of vitamin Mice on regular diet had increased E fed for up levels of Ab1-40 and Ab1-42 compared to preinjury to sham-injured mice (p < 0.05), and 8 weeks significantly higher level of Ab1-42 in postinjury the cortex and hippocampus compared to mice on vitamin E supplementation (p < 0.01).

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97 ANTIOXIDANTS TABLE 7-1 Continued Type of Injury/ Type of Study Reference Insult and Subjects Treatment Findings/Results Inci et al., Mild (200 g × Guinea pigs, Preinjury, Compared to uninjured controls, all α-tocopherol 1998 cm) and severe aged 3–4 injured guinea pigs had higher levels of (1,000 g × cm) months injection (100 lipid peroxides. Highest level of lipid TBI mg/kg) 8 hours peroxide was observed in untreated before injury guinea pigs that underwent severe TBI. Levels of lipid peroxide increased over time in guinea pigs with severe TBI regardless of treatment. And lipid peroxide levels decreased over time in guinea pigs with mild TBI, regardless of treatment. a n: sample size. b RR: relative risk. c CI: confidence interval. d I2: degree of heterogeneity. e HR: hazard ratio. f OR: odds ratio. 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],

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98 NUTRITION AND TRAUMATIC BRAIN INJURY 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 supple- mentation was not associated with total stroke. However, when stroke subtypes were ana- lyzed, 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 vi- tamin 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 supplementa- tion 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

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99 ANTIOXIDANTS 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 Refer- ence 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 impair- ment 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.

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100 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-2 Relevant Data Identified for Vitamin C Type of Injury/ Type of Study and Reference Insult Subjects Treatment Findings/Results Tier 1: Clinical trials Razmkon TBI (Glasgow Multi-center, Postinjury, The high dose of vitamin C stabilized et al., Coma Scale randomized, vitamin E or reduced the diameter of peri-lesional 2010 scores of 8 double-blind, (intravenously at edema/infarct in 68% of patients or less and placebo-controlled 400 IU daily for (p=0.01). radiologic trial 7 days) No adverse effects were observed. diagnoses of n=100 (83 male) Postinjury, diffuse axonal vitamin C (500 injury) mg daily for 7 days or 10 g on the day of admission and 4 days later), or placebo Sesso Cardiovascular Randomized, 500 mg/day of The cumulative incidence rate of major et al., events (MI, double-blind, vitamin C or cardiovascular events per year for 2008 stroke, or CVD placebo-controlled placebo vitamin E and placebo were similar. death) trial (Physicians’ Vitamin C had no significant treatment Health Study II) or preventive effect on the individual n=14,641 U.S. incidence of MI, stroke, or total male physicians, mortality. aged 50 years or Vitamin C treatment did not benefit men older with previous cardiovascular diseases at 8-year follow-up baseline. No interaction with vitamin E was found for any of the cardiovascular events. Compared to placebo, no significant adverse effects of vitamin C were observed. Cook Cardiovascular Randomized, Vitamin C (500 Vitamin C had no significant effect on et al., events (MI, double-blind, mg/day), vitamin major CVD morbidity and mortality E (600 IU d-α 2007 stroke, coronary placebo-controlled (RR=1.02). revascularization, trial (Women’s tocopherol There was no significant difference in or CVD death) Antioxidant acetate every cumulative incidence rate of CVD events Cardiovascular other day), or between subjects taking vitamin C and Study) beta carotene those taking placebo. (50 mg every n=8,171 other day) Subjects taking both vitamins C and female health E had significantly fewer strokes professionals, aged than those taking placebos for both 40 years or older vitamins (RR=0.69, 95% CI: 0.49–0.98; mean p=0.04), suggesting an interaction (p for follow-up=9.4 interaction=0.02). years No statistically significant adverse effects were observed.

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101 ANTIOXIDANTS TABLE 7-2 Continued Type of Injury/ Type of Study and Reference Insult Subjects Treatment Findings/Results Polidori Ischemic stroke Randomized, Postinjury, Barthel Index (BI): There was no et al., open-label trial vitamin C difference between treatment group 2005 (200 mg/day) + and control group at baseline or after n=59 aspirin (300 mg/ 3 months. But BI of subjects in both day) or aspirin groups increased over the study period (p < 0.05). only Plasma vitamin C: Levels were higher in the vitamin C plus aspirin group compared to control group, both in the first week (p < 0.02) and over the entire study period (p < 0.01). Plasma 8,12-isoprostane F2α-VI: Levels decreased in both groups over the study period. But vitamin C plus aspirin group had significantly lower levels than control group from day 1 to day 7 (p=0.01); the difference between the two groups from day 1 to day 90 was not significant. There was no correlation between plasma vitamin C level and levels of 8,12-isoprostane F2α-VI. No adverse effects were observed. Tier 2: Observational studies Kodama Subarachnoid n=217 Cisternal The clinical outcomes of 80.6% et al., hemorrhage with irrigation of patients (n=175) were rated as 2000 a significant risk therapy with “excellent” or “good” at hospital for symptomatic urokinase (120 discharge, while the morbidity (those vasospasm IU/mL) and rated as “fair” or “poor”) rate was (Fisher CT ascorbic acid (4 16.6% (n=36), the mortality rate was group 3 and CT mg/mL) 2.8% (n=6), and 2.8% of patients number > 60) developed vasospasm (n=6). None of the deaths were caused by vasospasm. Mean total drained blood volume was 113.7±12.0 mL; volume from red blood cell count was 96.5±9.6 mL, and from cell-free Hb count was 17.2±2.4 mL. Average total drainage from subjects who developed vasospasm during the study was 46.0 mL. Ascorbic acid absorption was determined by reduction in value of oxy- hemoglobin (Oxy-Hb) peak. Compared to patients who only had cisternal drainage, those who had cisternal irrigation had decreased Oxy-Hb value. Complications from irrigation include seizure (0.9%, n=2), meningitis infection (0.9%, n=2), and intracranial hemorrhage (1.9%, n=4). continued

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102 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 7-2 Continued Type of Injury/ Type of Study and Reference Insult Subjects Treatment Findings/Results Rabadi Ischemic stroke Retrospective, Postinjury, There was no significant difference and matched, case- 1,000 mg of between the two groups in terms of Kristal, control trial vitamin C per changes in total functional independence 2007 day measure score, functional independence n=46, aged 49–89 measure-cognition score, or functional years Control group independence measure–motor score. did not take vitamin C There was no difference in length of stay and whether patient was discharged to home or a long-term care facility. No adverse effects were mentioned. Tier 3: Animal studies None found Uses and Safety The EAR for vitamin C was based on maintaining near-maximal neutrophil concentra- tions 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

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103 ANTIOXIDANTS 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 associ- ated 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 associa- tion 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 pathol- ogy 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 partici- pants (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

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104 NUTRITION AND TRAUMATIC BRAIN INJURY 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 acti- vated 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, includ- ing 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 abun- dant 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 fol- lowing 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

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105 ANTIOXIDANTS after injury. For example, while the results from animal trials with vitamin E are encourag- ing, 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 combina- tion of various antioxidants including vitamins E, C, and carotenoids might be more effica- cious. 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). REFERENCES Berger, M. M., L. Soguel, A. Shenkin, J. P. Revelly, C. Pinget, M. Baines, and R. L. Chiolero. 2008. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Critical Care 12(4):R101. Bjelakovic, G., D. Nikolova, L. L. Gluud, R. G. Simonetti, and C. Gluud. 2007. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. The Journal of the American Medical Association 297(8):842–857. Blot, W. J., J.-Y. Li, P. R. Taylor, W. Guo, S. Dawsey, G.-Q. Wang, C. S. Yang, S.-F. Zheng, M. Gail, G.-Y. Li, Y. Yu, B.-q. Liu, J. Tangrea, Y.-h. Sun, F. Liu, J. F. Fraumeni, Y.-H. Zhang, and B. Li. 1993. Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of the National Cancer Institute 85(18):1483–1491. Buring, J. E. 2006. Aspirin prevents stroke but not MI in women; vitamin E has no effect on CV disease or cancer. Cleveland Clinic Journal of Medicine 73(9):863–870. Childs, A., C. Jacobs, T. Kaminski, B. Halliwell, and C. Leeuwenburgh. 2001. Supplementation with vitamin C and n-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Free Radical Biology and Medicine 31(6):745–753. Collaborative Group of the Primary Prevention Project. 2001. Low-dose aspirin and vitamin E in people at cardio- vascular risk: A randomised trial in general practice. Collaborative group of the primary prevention project. Lancet 357(9250):89–95. Conte, V., K. Uryu, S. Fujimoto, Y. Yao, J. Rokach, L. Longhi, J. Q. Trojanowski, V. M. Lee, T. K. McIntosh, and D. Pratico. 2004. Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. Journal of Neurochemistry 90(3):758–764. Cook, N. R., C. M. Albert, J. M. Gaziano, E. Zaharris, J. MacFadyen, E. Danielson, J. E. Buring, and J. E. Manson. 2007. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women—results from the women’s antioxidant cardiovascular study. Archives of Internal Medicine 167(15):1610–1618. Daga, M. K., Madhuchhanda, T. K. Mishra, and A. Mohan. 1997. Lipid peroxide, beta-carotene and alpha- tocopherol in ischaemic stroke and effect of exogenous vitamin E supplementation on outcome. Journal of the Association of Physicians of India 45(11):843–846. Eghwrudjakpor, P. O., and A. B. Allison. 2010. Oxidative stress following traumatic brain injury: Enhancement of endogenous antioxidant defense systems and the promise of improved outcome. Nigerian Journal of Medicine 19(1):14–21. Eidelman, R. S., D. Hollar, P. R. Hebert, G. A. Lamas, and C. H. Hennekens. 2004. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Archives of Internal Medicine 164(14):1552–1556.

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