16
Zinc

The trace element zinc is essential to at least 80 different enzymes in the human central nervous system (CNS), including DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) polymerases, metalloproteinases, and many dehydrogenases in intermediary metabolism, such as lactate dehydrogenase and pyruvate carboxylase (Tapiero and Tew, 2003). Zinc also is a structural component of a family of DNA-binding transcription factors known as zinc-finger proteins that are essential for gene expression (Klug and Schwabe, 1995; O’Halloran, 1993). Nuclear receptors, such as those that mediate the transcriptional roles of thyroid hormones, glucocorticoids, retinoic acid, vitamin D, and estrogen, are all zinc-finger proteins (Freedman and Luisi, 1993), and function as key players in the CNS.

ZINC AND THE BRAIN

In addition to the zinc that is bound to enzymes, transcription factors, and other proteins, about 10 percent of CNS zinc is in the free form and is associated with presynaptic vesicles of glutamatergic neurons. Although neurons containing free zinc are found in many regions of the brain, including the cortex, amygdala, and olfactory bulb, the neurons of the hippocampus have the highest concentrations of free zinc. The zinc in these vesicles is released into the synaptic cleft, where it modulates the activity of a variety of postsynaptic receptors including N-methyl-D-aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors, and voltage-gated calcium channels (Matias et al., 2006; Stoll et al., 2007). Regulation of NMDA receptor subunit expression also has been shown to be regulated by zinc (Levenson, 2006).

In addition to the important neuromodulatory roles of free zinc, it has been repeatedly shown that excessive release of zinc from synaptic boutons can result in postsynaptic neuronal death. Neurons in brain regions with high concentrations of free zinc, such as the hippocampus, are thus particularly vulnerable to zinc-mediated damage and death. Additionally, after CNS injury, large quantities of free zinc can be released, not only from presynaptic vesicles but also from metalloproteins and from mitochondrial zinc pools, result-



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16 Zinc The trace element zinc is essential to at least 80 different enzymes in the human central nervous system (CNS), including DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) polymerases, metalloproteinases, and many dehydrogenases in intermediary metabolism, such as lactate dehydrogenase and pyruvate carboxylase (Tapiero and Tew, 2003). Zinc also is a structural component of a family of DNA-binding transcription factors known as zinc- finger proteins that are essential for gene expression (Klug and Schwabe, 1995; O’Halloran, 1993). Nuclear receptors, such as those that mediate the transcriptional roles of thyroid hormones, glucocorticoids, retinoic acid, vitamin D, and estrogen, are all zinc-finger proteins (Freedman and Luisi, 1993), and function as key players in the CNS. ZINC AND THE BRAIN In addition to the zinc that is bound to enzymes, transcription factors, and other pro- teins, about 10 percent of CNS zinc is in the free form and is associated with presynaptic vesicles of glutamatergic neurons. Although neurons containing free zinc are found in many regions of the brain, including the cortex, amygdala, and olfactory bulb, the neurons of the hippocampus have the highest concentrations of free zinc. The zinc in these vesicles is released into the synaptic cleft, where it modulates the activity of a variety of postsynaptic receptors including N-methyl-D-aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors, and voltage-gated calcium channels (Matias et al., 2006; Stoll et al., 2007). Regulation of NMDA receptor subunit expression also has been shown to be regu- lated by zinc (Levenson, 2006). In addition to the important neuromodulatory roles of free zinc, it has been repeat- edly shown that excessive release of zinc from synaptic boutons can result in postsynaptic neuronal death. Neurons in brain regions with high concentrations of free zinc, such as the hippocampus, are thus particularly vulnerable to zinc-mediated damage and death. Additionally, after CNS injury, large quantities of free zinc can be released, not only from presynaptic vesicles but also from metalloproteins and from mitochondrial zinc pools, result- 233

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234 NUTRITION AND TRAUMATIC BRAIN INJURY ing in neuronal damage and death in a variety of brain regions (Frederickson et al., 2004; Sensi and Jeng, 2004). Traumatic brain injury (TBI) induces a variety of damaging oxidative processes, and a number of studies show a role for zinc deficiency in the induction of reactive oxygen species (ROS). Zinc deficiency may therefore exacerbate the oxidative damage associated with TBI. This hypothesis is supported by work in cultured rat neurons (differentiated PC12 cells) showing that deficiencies in extracellular zinc resulted in an increase in neuronal oxida- tion via the activation of the NMDA receptor. This in turn led to calcium influx and to the calcium-mediated activation of protein kinase C/NADPH (nicotinamide adenine dinucleo- tide phosphate) oxidase as well as nitric oxide synthase (Aimo et al., 2010). Other work has implicated zinc deficiency in mitochondrial accumulation and release of ROS (Corniola et al., 2008). This mechanism is dependent on the tumor suppressor protein p53. Nuclear targets of p53 in zinc deficiency include genes that arrest the cell cycle and induce apoptotic mechanisms leading to cell death (Corniola et al., 2008). Finally, in response to TBI, anti- oxidant mechanisms are increased in the brain. For example, increases in several isoforms (I, II, and III) of the zinc- and copper-binding protein metallothionein have been reported after brain injury (Penkowa et al., 2001; Yeiser et al., 1999). Zinc deficiency blunts this response. Because the metal-binding metallothioneins have been shown to play an antioxidant role, these data suggest that zinc deficiency may impair antioxidant mechanisms that are needed to protect neurons and other cell types in the brain after TBI. A relevant selection of human and animal studies (from the year 1990) examining the effectiveness of zinc supplementation on providing resilience or treating TBI in the acute and subacute phases of injury is presented in Table 16-1. This table also includes some sup- porting evidence from human studies on zinc supplementation for other CNS injuries, such as stroke and seizure. The occurrence or absence of adverse effects in humans is included if reported by the authors. USES AND SAFETY Dietary requirements for zinc are determined not only by the roles of zinc in the brain, but also by the necessity of adequate zinc for immune function, tissue repair and replace- ment, nutrient digestion, and energy metabolism in all organ systems. There is, however, no single widely accepted or routinely available biomarker for zinc status (IOM, 2006). Marginal zinc deficiency is particularly difficult to identify and is thus likely to go unrecog- nized. The Committee on Mineral Requirements for Cognitive and Physical Performance of Military Personnel (IOM, 2006) reported that high-intensity exercise can increase urinary zinc excretion by 20–40 percent. This, combined with severe environmental conditions that promote sweating, means that many active-duty military personnel have high zinc losses. These losses must be replaced by dietary intake. The current Recommended Dietary Allowance (RDA) for zinc in the general population is 9 mg/day for females between the ages of 14 and 18, 8 mg/day for females 19 years and older, and 11 mg/day for males 14 years and older. In the general population, data from the National Health and Nutrition Examination Survey (2002) suggest that 11 percent of males and 17 percent of females have regular intakes below the recommended amounts. Owing to the increased requirements resulting from physical activity and potential increased excre- tion (via sweat and urine, as well as increased muscle turnover), the Military Daily Recom- mended Intake (MDRI) for zinc is 12 mg/day for females and 15 mg/day for males (IOM, 2006). Revisions to the MDRIs, based on current DRIs, are imminent. Because of zinc’s important role in the modulation of immunity, zinc supplements have

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235 ZINC TABLE 16-1 Relevant Data Identified for Zinc Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Aquilani Subacute Randomized, Postinjury, Compared to baseline values, all Zn2+ supplementation at et al., stroke prospective, patients had significantly greater daily 2009 patients placebo- 10 mg/day or placebo carbohydrate (p=0.03) and zinc intake (p < 0.001) and lower National Institute of with low controlled, Health Stroke Scale (NIHSS) scores (p < Zn2+ intake double-blind (< 6.6 mg/ trial 0.001) at 30 days. day) na=26 Compared to patients assigned to placebo, patients assigned to zinc supplementation had greater body weight (p=0.002), daily energy intake (p=0.02), protein intake (p=0.04), lipid intake (p=0.01), and zinc level (p < 0.001) at 30 days. Zinc-treated patients also had higher level of serum albumin (p=0.001) and greater improvement in NIHSS score (p=0.04) than controls. And zinc intake was inversely correlated to NIHSS score (rb=−0.46, p < 0.02). No adverse effects of zinc were mentioned. Young Severe TBI Randomized, Postinjury, Although there was no difference et al., prospective, elemental zinc at between the standard (2.5 mg) group 1996 double-blind, standard level of 2.5 and the supplemented (12 mg) group placebo- mg or supplementation on serum zinc level, the supplemented controlled at 12 mg for 15 days, group had significantly higher levels of trial then tablets of 22 mg zinc in urine at days 2 (p=0.0001) and 10 elemental zinc or placebo (p=0.01). But the significance disappeared n=68 TBI for 3 months at week 3. patients Supplemented group also had higher mean serum pre-albumin level (p=0.003) and mean retinol-binding protein levels (p=0.01) at 3 weeks. After adjusting for baseline value, supplemented group had higher mean Glasgow Coma Scale (GCS) score at day 28 (p=0.03) and mean motor GCS score at days 15 (p=0.005) and 21 (p=0.02), although there was no statistically significant difference in the raw GCS scores. No adverse effects were mentioned. Tier 2: Observational studies None found continued

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236 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 16-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 3: Animal studies Hellmich TBI Adult, male Calcium Compared to saline-treated rats, rats et al., Sprague- ethylenediaminetetraacetic pretreated with CaEDTA had significantly 2008 Dawley rats acid (EDTA) fewer Flouro-Jade (FJ, showing injured cells) stained cells in CA1 (p < 0.05) and rats treated with CaEDTA after TBI had reduced FJ-stained cells in CA3 (p < 0.02). Although both pre- and postinjury administration of CaEDTA increased the expression of antiapoptotic gene Bcl-2, only pretreatment was significant when compared to saline-treated rats (p < 0.05). And only postinjury treatment with CaEDTA increased the expression of Bax (p < 0.05 vs. saline-treated and pretreated rats) and caspase 3 genes (p < 0.05 vs. saline-treated rats only). CaEDTA treatment had no significant effect on spatial memory. And injured rats with and without CaEDTA treatment and treated, sham-injured rats all had significantly worse performance on the Morris water maze test (p < 0.05) compared to untreated, sham-injured rats. Hellmich TBI, fluid Adult, male Lamotrigine or At 4 hours post-TBI, injured rats had et al., percussion Sprague- nicardipine significant increase in number of neurons 2007 injury (FPI) Dawley rats with Flouro-Jade (FJ, showing injured cells) and Newport Green (NG, showing zinc positive cells) staining in CA1, CA3, and dentate gyrus regions of the hippocampus (p < 0.05). At 24 hours after injury, increased number of FJ- and NG-positive cells was seen in the CA1 and CA2 regions (p < 0.05), with stained cells seen in rats with severe injury. In the dentate gyrus, increase in stained cells was seen only in moderately injured rats (p < 0.05). Both lamotrigine and nicardipine led to a decrease on FJ- and NG-stained neurons in CA1 (p < 0.05), and lamotrigine led to decrease of stained cells in CA3 (p < 0.05). There was no significant difference in the expression of Bcl-2, caspase 3 and caspase 9, and Hsp 70 between the two staining methods. However, within-rat variability was smaller for FJ staining than NG.

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237 ZINC TABLE 16-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Hellmich TBI, FPI Male Preinjury, Treatment with EDTA was significantly et al., Sprague- calcium EDTA (100mM) associated with increased expression of 2004 Dawley rats 30 minutes before injury neuroprotective genes and antioxidant or no treatment enzymes. EDTA also significantly increased expression of cell cycle regulatory genes and reduced apoptotic cell death after TBI up to 85%. Results were consistent with microarray studies describing changes in the expression of genes in several signaling and cellular pathways after TBI. Yeiser TBI, Adult, male Postinjury, Compared to rats fed with standard et al., unilateral Sprague- zinc diets (standard: amount of zinc (controls), serum 2002 cortical stab Dawley rats 30 mg/kg; moderately zinc level was significantly lower in zinc-deficient rats (p ≤ 0.05) and was wounds deficient: 5 mg/kg; and supplemental: 180 mg/kg) not significantly different in zinc- supplemented rats. There was no significant between-group difference regarding zinc levels in the brain. Compared to controls, deficient rats had greater number of cells stained with terminal deoxynucleotidyl transferase dUTP nick end labeling (p ≤ 0.05). continued

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238 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 16-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Penkowa TBI Adult, male Preinjury, normal diet Compared to uninjured controls, et al., Sprague- (43.3 mg Zn/kg, 6.5 mg zinc-deficient rats had lower food 2001 Dawley rats Cu/kg), zinc-deficient diet consumption, lower level of brain zinc, and decreased weight gain (p < 0.05 (1.9 mg Zn/kg), copper- deficient diet (0.8 mg Cu/ for all three). Zinc-deficient rats had kg), or zinc pair-fed diet decreased weight gain compared to pair- fed rats, too (p < 0.05). (43.3 mg Zn/kg) Injured, zinc-deficient rats had greater number of round hypertrophic microphages at the periphery of the lesion and in the parenchyma than injured, normally fed rats (p < 0.05) and uninjured controls (p < 0.001). Both injured and uninjured zinc-deficient rats had decreased astrogliosis around the lesion and long thin processes than corresponding normally fed rats (p < 0.05 for both). Injured zinc-deficient rats had more apoptotic cells (neurons, astrocytes, and microglia/microphages) than uninjured controls (p < 0.001) and injured normally fed rats (p < 0.05). Expression of metallothionein (MT) isoforms I and II in injured, zinc-deficient rats was greater compared to uninjured controls (p < 0.001), but lower compared to injured, normally fed rats (p < 0.05). Expression of MT-III was higher in injured, zinc- deficient rats compared to both controls (p < 0.001) and injured, normally fed rats (p < 0.05). Analysis of oxidative stress markers showed that injured, zinc-deficient rats had increased levels of MDA (malondialdehyde), NITT (protein tyrosine nitration), and NF-κB (nuclear factor kappa B) compared to both uninjured controls (p < 0.001 for all three markers) and injured, normally fed rats (p < 0.05 for all three).

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239 ZINC TABLE 16-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Suh Moderate Male Postinjury, Vesicular zinc was loss from boutons in et al., and severe Sprague- calcium EDTA (for ion impacted area within 6 hours of injury. 2000 TBI, Dawley rat zinc chelation), zinc- In rats that underwent severe trauma, induced by EDTA (prevents zinc neurons stained with N-(6-methoxy-8- weight drop chelation), or saline quinolyl)-para-toluenesulfonamide (TSQ) model can be seen 1 hour after TBI, especially in the hilar and infragranular regions in dentate gyrus. TSQ-labeled neurons can be seen in the cortex and thalamic regions after 24 hours. The main difference between severe and moderate trauma was there was more florescent neurons in the dentate granule layer and subgranular hilar regions. Results from TSQ florescence were confirmed by eosin staining showing neuron degeneration. Administration of calcium EDTA reduced the number of eosinophilic neurons in the dentate gyrus, hilus, and CA1 regions (p < 0.05 vs. saline for all three). The number of eisonophilic neurons was not affected by zinc-EDTA. a n: sample size. b r: correlation coefficient. been used in a variety of settings to improve immune function and reduce inflammation (see Prasad, 2009; Scrimgeour and Condlin, 2009 for recent reviews). A 2008 meta-analysis of the four available randomized trials of zinc supplementation and clinical outcomes in critically ill patients showed only small, statistically insignificant improvements in mortality and length of stay in intensive care (Heyland et al., 2008). However, zinc supplementation appears to be associated with improvements in markers of immune function in a variety of other noncritically ill patients. For example, a 2010 report showed that 18 months of daily zinc supplementation (12 mg for women and 15 mg for men) significantly reduced the likeli- hood of immunological failure, rate of diarrhea, and mortality in HIV-infected adults (Baum et al., 2010). The use of zinc to treat cold and flu symptoms also has become very popular, albeit with conflicting scientific evidence on efficacy. Although some studies have reported no improvements in cold symptoms (Eby and Halcomb, 2006), a meta-analysis of double-blind, randomized, controlled trials suggested that zinc gluconate may be effective in reducing the symptoms and duration of the common cold in healthy people when administered within 24 hours of onset of symptoms (Singh and Das, 2011). To produce these effects, however, the daily dose varied between 30 mg zinc in syrup preparation and 80–190 mg zinc in lozenge form (Singh and Das, 2011). This raises the issue of zinc overload. Currently, the Tolerable Upper Intake Level (UL) for zinc is set at 40 mg/day; the minimum effective dose discussed for treatment of colds

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240 NUTRITION AND TRAUMATIC BRAIN INJURY would significantly exceed this amount. A number of recent reports have shown that pro- longed excessive zinc overload from misuse of dental preparations results in potentially fatal copper deficiency, characterized by pancytopenia and myelopolyneuropathy (Afrin, 2010; Hedera et al., 2009). These data suggest that recommendations to supplement zinc for any reason, including for the treatment of TBI, should include cautionary advice not to chroni- cally exceed the UL for zinc intake. EVIDENCE INDICATING EFFECT ON RESILIENCE Human Studies As with other nutrients or food components, the committee found no human studies that have examined the potential benefits of zinc in TBI or in other related diseases or conditions included in the review of the literature (subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy). Animal Studies Given the evidence, both clinical and experimental, showing a possible role for the use of zinc as a treatment in TBI, a 2010 study (Cope et al., unpublished) sought to test the hypothesis that zinc supplementation prior to injury could increase resilience and improve outcomes of brain injury. The effect of diet was assessed using the controlled cortical injury model of TBI in adult rats. This model of severe injury induced anhedonia, a depression-like symptom, in the rat, as measured by the two-bottle saccharin preference test. Although this symptom was observed in injured animals that were fed a diet with adequate zinc (30 ppm), four weeks of zinc supplementation (180 ppm) prior to the injury prevented the appearance of anhedonia following TBI. Animals also were monitored for the appearance of anxiety-like behaviors. Four weeks of a diet with marginal zinc deficiency (5 ppm) resulted in anxiety, as measured by the elevated plus maze, even in the absence of brain injury. The development of anxiety has been previously reported in zinc-deficient rats (Takeda et al., 2008; Tassabehji et al., 2008) and reviewed in 2010 (Cope and Levenson). The earlier reports used diets that were more severely limited in zinc (< 3 ppm), used weanling animals that are highly susceptible to zinc deficiency, or both. The most recent work is the first report to show that even diets margin- ally deficient in zinc may result in anxiety. Cortical injury produced additional evidence of anxiety; however, animals fed the zinc-supplemented diet prior to injury appeared to have greater resilience to the effects of injury on anxiety. Not only did supplementation partially prevent anxiety-like behaviors, supplemented animals also showed prevention of significant increases in adrenal weight measured two weeks after TBI (Cope et al., unpublished). Because loss of cognitive function can be one of the most debilitating deficits associated with TBI, the 2010 study also examined whether zinc supplementation could prevent losses in spatial learning and memory. While controlled cortical impact resulted in significant performance deficits on the Morris water maze test in animals fed a diet adequate in zinc, rats that were fed the zinc-supplemented diet (180 ppm) prior to TBI showed no differences from sham-operated control rats at any point during the 10-day cognitive trial, suggesting that zinc supplementation may improve cognitive resilience in the event of brain injury (Cope et al., unpublished). Future work will be needed to determine the possible uses of zinc supplementation to improve resilience across the range of traumatic brain injuries, including mild TBI.

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241 ZINC EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies Traumatic brain injury results in significantly depressed serum zinc levels as well as increased urinary zinc excretion. A 1986 report showed that urinary zinc excretion was proportional to the severity of the brain injury (McClain et al., 1986). The most severely injured patients in this study had mean urinary zinc levels that were 14 times normal values, suggesting rapid zinc depletion. Additionally, patients with severe head injuries develop hy- poalbuminemia (most likely secondary to increased interleukin-1-mediated transendothelial movement of albumin), as well as evidence of inflammation, including increases in acute- phase proteins (e.g., C-reactive protein, ceruloplasmin), and elevated white blood cell counts (McClain et al., 1988; Young et al., 1988). The impact of these factors on zinc availability and zinc metabolism is potentially significant. Because albumin is the major serum transport protein for zinc, hypoalbuminemia would potentially impair both zinc transport and avail- ability. Induction of cytokines such as interleukin-1 may further compromise zinc availability and reduce zinc stores that are already significantly depleted by increased urinary excretion. Given the apparent role of TBI in compromising zinc status, Young et al. (1996) sought to test the effectiveness of using zinc supplementation after TBI to reduce zinc losses, maintain protein balance, and improve neurological outcomes. Within 72 hours of injury, 68 patients with severe closed head injuries were randomly assigned to either an adequate zinc (2.5 mg/day) or supplemental zinc (12 mg/day) treatment group. These zinc levels were administered intravenously as zinc sulfate in conjunction with total parenteral nutrition. Supplements were administered in a double-blind fashion for the initial 15 days and followed by 22 mg intravenous zinc (as zinc gluconate) or placebo for the remainder of the study. Zinc supplementation resulted in increased levels of serum pre-albumin and retinol-binding protein, suggesting improved protein synthesis and a role for supplemental zinc in maintaining visceral protein in TBI patients. Two weeks after injury, patients in the zinc-supplemented group had better Glasgow Coma Scale scores than control patients given adequate zinc. These improvements were maintained at 21 and 28 days. Interestingly, the differences between the groups were seen despite the fact that neither serum zinc concentra- tions nor zinc levels in cerebral spinal fluid were changed by zinc supplementation, suggest- ing that the zinc is taken up into tissues after administration, and illustrating the fact that serum zinc levels are not a good indicator of zinc status. One month after TBI, mortality in the control group receiving adequate zinc was 26 percent, compared to 12 percent in the group receiving supplemental zinc. Caution should be exercised, however, when interpret- ing the mortality data, because a larger number of patients in the control group (13 vs. 6 in the zinc-supplemented group) required craniotomies for hematoma evacuation during the course of the study. The efficacy of treatment with zinc also has been tested after ischemic injury. A small (26 patients assigned to receive either zinc supplementation or placebo) human study sought to explore the effectiveness of replacing zinc in stroke patients who had dietary zinc intakes that were lower than two-thirds of the RDA. In these patients, zinc replacement (10 mg/ day) improved outcomes measured by the National Institutes of Health Stroke Scale 30 days after stroke (Aquilani et al., 2009). Although this work does not address the effect of zinc supplementation using levels that are higher than the RDA as a treatment for neuronal injury, it does suggest that, at the very least, maintaining adequate zinc levels after injury is important for recovery. Finally, as many as 40 percent of patients hospitalized with TBI develop major depres-

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242 NUTRITION AND TRAUMATIC BRAIN INJURY sion, making it the most common long-term complication of TBI (Jorge and Starkstein, 2005). Although there are no data on the use of supplemental zinc to improve antidepressant drug treatment in patients with TBI-associated depression and although this report does not further review long-term health disorders associated with TBI, the use of zinc to improve mood may be effective among this patient population. Animal Studies Zinc Deficiency Because military personnel may be at risk for developing zinc deficiency, and TBI further increases zinc losses, it is important to understand the possible effects of zinc deficiency on the cellular and molecular mechanisms associated with TBI. Animal models not only per- mit the study of these mechanisms in a controlled fashion, but also have provided useful information about the role of zinc in TBI. For example, an examination of DNA damage after infliction of a unilateral cortical stab wound in adult rats found that zinc deficiency (induced with a moderately deficient diet that did not result in anorexia) led to a significant increase in terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL)-positive cells at the site of injury compared to animals with adequate zinc. TUNEL staining, a marker of DNA fragmentation and cell death, in combination with nuclear morphology and cell-specific markers, revealed that moderate zinc deficiency caused both apoptosis and necrosis of macrophages and ameboid microglia involved in the clearance of debris following TBI (Yeiser et al., 2002). More severely zinc-deficient diets that induced anorexia resulted in increased neuronal death and significant increases in gliosis at the site of injury (Penkowa et al., 2001). These data combine to suggest that zinc deficiency not only increases the severity of damage after TBI, but also may prevent debris clearance and inhibit repair at the site of the injury. Zinc Toxicity Animal models also have been used to show that TBI can result in the accumulation of free zinc that leads to neuronal death (Hellmich et al., 2004; Yeiser et al., 1999). In addi- tion to affecting the site of injury, TBI produced either by fluid percussion injury (Hellmich et al., 2004) or mechanical cortical trauma (Suh et al., 2000) resulted in neuronal death in the dentate gyrus, hilus, and CA1 regions of the hippocampus. Not only does the neuronal death appear to be associated with presynaptic zinc release (Hellmich et al., 2007), but also the cell death was largely prevented by treatment with the zinc chelator calcium disodium ethylenediamine tetraacetate (Hellmich et al., 2004, 2008), suggesting that zinc in high concentrations after TBI is neurotoxic. Despite histological evidence of neuronal survival, however, chelation of zinc after TBI did not improve the spatial memory deficits associated with brain injury (Hellmich et al., 2008). This understanding of the possible role of free zinc in neuronal death raises the ques- tion of whether clinicians should be treating brain-injured patients with supplemental zinc, particularly in acute periods after severe injury when the blood-brain barrier that regulates brain zinc uptake has been disrupted. An animal model of TBI showed that four weeks of dietary zinc supplementation (180 ppm) after TBI did not significantly increase cell death (as measured by TUNEL labeling) in any cell type examined, including microglia, macro- phages, neurons, or oligodendrocytes at the site of injury or any other region of the CNS (Yeiser et al., 2002). These data suggest that concerns about the potential neurotoxicity of

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243 ZINC enteral zinc supplementation in TBI patients are unwarranted. Reports that intraperitoneal injections of zinc significantly increased the infarct size and impaired motor behavior after focal ischemia in subject rats suggest, however, that caution is warranted when using zinc parenterally in moderately to severely injured patients (Levenson, 2005; Shabanzadeh et al., 2004). CONCLUSIONS AND RECOMMENDATIONS Although the available evidence suggests that zinc may be an effective treatment for TBI, there are many unanswered questions that prevent its optimal use in the clinical set- ting. Future research will be needed to determine the best practices for zinc administration after TBI and to populations at risk of TBI. The safety of zinc supplementation, especially in patients with moderate to severe TBI, also must be evaluated. In the acute care situation, the available clinical evidence suggests that after TBI, zinc deficiency should be prevented to maintain visceral protein and optimize the potential for neurological recovery. The only acute dose of supplemental zinc that has been tested in a clinical setting is 12 mg/day administered intravenously for the first 15 days after injury. After day 15, an oral dose of 22 mg/day was used. With the UL set at 40 mg/day, these doses are not likely to have adverse effects. However, the impact of parenteral administration of zinc has not been independently investigated, nor has it been compared to enteral feeding in a TBI model. Doses of up to 30 mg/day have been provided to critically ill patients without obvious adverse clinical impacts. Although there have been no studies to determine the possible efficacy of zinc supple- mentation in TBI patients who are being treated for depression and depression-related dis- orders, the available clinical evidence suggests that this approach may be warranted. RECOMMENDATION 16-1. Based on a report showing efficacy in humans, the com- mittee recommends that animal studies be conducted to determine the best practices for zinc administration after concussion/mild, moderate, and severe TBI, such as determin- ing the therapeutic window for zinc administration, the length of treatment time for greatest efficacy, and the optimal level of zinc to improve outcomes. These trials should also evaluate the safety of zinc, based on concerns about toxicity and overload. Results from these studies should be used to design human clinical trials using zinc as a treat- ment for TBI. RECOMMENDATION 16-2. Future work is needed in both humans and animal mod- els to determine the extent to which chronic preinjury zinc supplementation can improve resilience in the event of a TBI. REFERENCES Afrin, L. B. 2010. Fatal copper deficiency from excessive use of zinc-based denture adhesive. American Journal of the Medical Sciences 340(2):164–168. Aimo, L., G. N. Cherr, and P. I. Oteiza. 2010. Low extracellular zinc increases neuronal oxidant production through NADPH oxidase and nitric oxide synthase activation. Free Radical Biology and Medicine 48(12):1577–1587. Aquilani, R., P. Baiardi, M. Scocchi, P. Iadarola, M. Verri, P. Sessarego, F. Boschi, E. Pasini, O. Pastoris, and S. Viglio. 2009. Normalization of zinc intake enhances neurological retrieval of patients suffering from ischemic strokes. Nutritional Neuroscience 12(5):219–225. Baum, M. K., S. H. Lai, S. Sales, J. B. Page, and A. Campa. 2010. Randomized, controlled clinical trial of zinc supplementation to prevent immunological failure in HIV-infected adults. Clinical Infectious Diseases 50(12):1653–1660.

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244 NUTRITION AND TRAUMATIC BRAIN INJURY Cope, E. C., and C. W. Levenson. 2010. Role of zinc in the development and treatment of mood disorders. Current Opinion in Clinical Nutrition and Metabolic Care 13(6):685–689. Cope, E. C., J. W. VanLandingham, A. G. Scrimgeour, and C. W. Levenson. (unpublished). Zinc supplementation improves behavioral resilience to traumatic brain injury in the rat. Corniola, R. S., N. M. Tassabehji, J. Hare, G. Sharma, and C. W. Levenson. 2008. Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Research 1237:52–61. Eby, G. A., and W. W. Halcomb. 2006. Ineffectiveness of zinc gluconate nasal spray and zinc orotate lozenges in common-cold treatment: A double-blind, placebo-controlled clinical trial. Alternative Therapies in Health and Medicine 12(1):34–38. Frederickson, C. J., W. Maret, and M. P. Cuajungco. 2004. Zinc and excitotoxic brain injury: A new model. Neuroscientist 10(1):18–25. Freedman, L. P., and B. F. Luisi. 1993. On the mechanism of DNA-binding by nuclear hormone receptors—A structural and functional perspective. Journal of Cellular Biochemistry 51(2):140–150. Hedera, P., A. Peltier, J. K. Fink, S. Wilcock, Z. London, and G. J. Brewer. 2009. Myelopolyneuropathy and pan- cytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc. Neurotoxicology 30(6):996–999. Hellmich, H. L., C. J. Frederickson, D. S. DeWitt, R. Saban, M. O. Parsley, R. Stephenson, M. Velasco, T. Uchida, M. Shimamura, and D. S. Prough. 2004. Protective effects of zinc chelation in traumatic brain injury correlate with upregulation of neuroprotective genes in rat brain. Neuroscience Letters 355(3):221–225. Hellmich, H. L., K. A. Eidson, B. A. Capra, J. M. Garcia, D. R. Boone, B. E. Hawkins, T. Uchida, D. S. Dewitt, and D. S. Prough. 2007. Injured fluoro-jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury. Brain Research 1127(1):119–126. Hellmich, H. L., K. Eidson, J. Cowart, J. Crookshanks, D. K. Boone, S. Shah, T. Uchida, D. S. DeWitt, and D. S. Prough. 2008. Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury. Neuroscience Letters 440(2):155–159. Heyland, D. K., N. Jones, N. Z. Cvijanovich, and H. Wong. 2008. Zinc supplementation in critically ill patients: A key pharmaconutrient? Journal of Parenteral and Enteral Nutrition 32(5):509–519. IOM (Institute of Medicine). 2006. Mineral requirements for military personnel: Levels needed for cognitive and physical performance during garrison training. Washington, DC: The National Academies Press. Jorge, R. E., and S. E. Starkstein. 2005. Pathophysiologic aspects of major depression following traumatic brain injury. Journal of Head Trauma Rehabilitation 20(6):475–487. Klug, A., and J. W. R. Schwabe. 1995. Protein motifs .5. Zinc fingers. The Federation of American Societies for Experimental Biology Journal 9(8):597–604. Levenson, C. W. 2005. Zinc supplementation: Neuroprotective or neurotoxic? Nutrition Reviews 63(4):122–125. Levenson, C. W. 2006. Regulation of the NMDA receptor: Implications for neuropsychological development. Nutrition Reviews 64(9):428–432. Matias, C. M., N. C. Matos, M. Arif, J. C. Dionisio, and M. E. Quinta-Ferreira. 2006. Effect of the zinc chelator N,N,N’,N’-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) on hippocampal mossy fiber calcium signals and on synaptic transmission. Biological Research 39(3):521–530. McClain, C. J., D. L. Twyman, L. G. Ott, R. P. Rapp, P. A. Tibbs, J. A. Norton, E. J. Kasarskis, R. J. Dempsey, and B. Young. 1986. Serum and urine zinc response in head-injured patients. Journal of Neurosurgery 64(2):224–230. McClain, C. J., B. Hennig, L. G. Ott, S. Goldblum, and A. B. Young. 1988. Mechanisms and implications of hy- poalbuminemia in head-injured patients. Journal of Neurosurgery 69(3):386–392. O’Halloran, T. V. 1993. Transition-metals in control of gene-expression. Science 261(5122):715–725. Penkowa, M., M. Giralt, P. S. Thomsen, J. Carrasco, and J. Hidalgo. 2001. Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes. Journal of Neurotrauma 18(4):447–463. Prasad, A. S. 2009. Zinc: Role in immunity, oxidative stress and chronic inflammation. Current Opinion in Clinical Nutrition and Metabolic Care 12(6):646–652. Scrimgeour, A. G., and M. L. Condlin. 2009. Zinc and micronutrient combinations to combat gastrointestinal inflammation. Current Opinion in Clinical Nutrition and Metabolic Care 12(6):653–660. Sensi, S. L., and J. M. Jeng. 2004. Rethinking the excitotoxic ionic milieu: The emerging role of Zn2+ in ischemic neuronal injury. Current Molecular Medicine 4(2):87–111. Shabanzadeh, A. P., A. Shuaib, T. Yang, A. Salam, and C. X. Wang. 2004. Effect of zinc in ischemic brain injury in an embolic model of stroke in rats. Neuroscience Letters 356(1):69–71. Singh, M., and Das, R. R. 2011. Zinc for the common cold. Cochrane Database of Systematic Reviews 2:CD001364. Stoll, L., J. Hall, N. Van Buren, A. Hall, L. Knight, A. Morgan, S. Zuger, H. Van Deusen, and L. Gentile. 2007. Differential regulation of ionotropic glutamate receptors. Biophysical Journal 92(4):1343–1349.

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245 ZINC Suh, S. W., J. W. Chen, M. Motamedi, B. Bell, K. Listiak, N. F. Pons, G. Danscher, and C. J. Frederickson. 2000. Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Research 852(2):268–273. Takeda, A., H. Itoh, K. Yamada, H. Tamano, and N. Oku. 2008. Enhancement of hippocampal mossy fiber activity in zinc deficiency and its influence on behavior. Biometals 21(5):545–552. Tapiero, H., and K. D. Tew. 2003. Trace elements in human physiology and pathology: Zinc and metallothioneins. Biomedicine and Pharmacotherapy 57(9):399–411. Tassabehji, N. M., R. S. Corniola, A. Alshingiti, and C. W. Levenson. 2008. Zinc deficiency induces depression-like symptoms in adult rats. Physiology and Behavior 95(3):365–369. Yeiser, E. C., A. A. Lerant, R. M. Casto, and C. W. Levenson. 1999. Free zinc increases at the site of injury after cortical stab wounds in mature but not immature rat brain. Neuroscience Letters 277(2):75–78. Yeiser, E. C., J. W. Vanlandingham, and C. W. Levenson. 2002. Moderate zinc deficiency increases cell death after brain injury in the rat. Nutritional Neuroscience 5(5):345–352. Young, A. B., L. G. Ott, D. Beard, R. J. Dempsey, P. A. Tibbs, and C. J. McClain. 1988. The acute-phase response of the brain-injured patient. Journal of Neurosurgery 69(3):375–380. Young, B., L. Ott, E. Kasarskis, R. Rapp, K. Moles, R. J. Dempsey, P. A. Tibbs, R. Kryscio, and C. McClain. 1996. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. Journal of Neurotrauma 13(1):25–34.

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