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Title: Nutritional treatment for traumatic brain injury.

Angus G. Scrimgeour Ph.D. and Michelle L. Condlin M.A.,R.D.

Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick,

Massachusetts, USA.

Angus Scrimgeour*, Military Nutrition Division, USARIEM, Kansas Street, Natick, MA 01760;
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

Tel: 508-233-5155; Fax: 508-233-4869; E-mail: angus.scrimgeour@us.army.mil

Michelle Condlin, Military Nutrition Division, USARIEM, Kansas Street, Natick, MA 01760;
Tel: 508-233-5685; Fax: 508-233-4869; E-mail: michelle.l.condlin.ctr@mail.mil
Journal of Neurotrauma

*corresponding author.

Running title: Nutrition support for TBI.

Table of Contents title: Nutritional treatment for traumatic brain injury.


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ABSTRACT Traumatic brain injury (TBI) is a significant public health concern. On average,

1.7 million people sustain a TBI annually and about 5.3 million Americans are living with a TBI-

related disability. As the leading cause of death and disability in persons under 45 years old,

there is a need for developing evidence-based interventions to reduce morbidity from this injury.

So far, despite encouraging preclinical results, almost all neuroprotection trials have failed to

show any significant efficacy in the treatment of clinical TBI. The cascade of molecular and

cellular changes following TBI involves plasticity in many different neurochemical systems,
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

which represent putative targets for neurotherapeutic interventions. Accordingly, a successful

TBI treatment may have to simultaneously attenuate many injury factors. The purpose of this

review is to highlight four promising nutritional intervention options that have been identified,
Journal of Neurotrauma

omega-3, zinc, vitamin D and glutamine, and to provide an up-to-date summary regarding their

apparent efficacy for affecting TBI.

KEYWORDS traumatic brain injury, review, omega-3, zinc, vitamin D, glutamine.


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INTRODUCTION Traumatic brain injury (TBI) is a contributing factor to a third of all injury-

related deaths in the U.S. The estimated economic cost of TBI in 2010 (including direct and

indirect medical costs), is estimated to be $76.5 billion 1. The incidence of mild TBI in combat

casualties has prompted recognition for the establishment of measures to increase TBI recovery

methods to hasten safe re-entry into the workforce, and treatments to minimize long-term and

delayed TBI-related debilitation. So far, despite encouraging preclinical results, almost all

pharmaceutical trials have failed to show any significant efficacy in the treatment of clinical TBI.
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

This may be due, in part, to the fact that most of the therapies investigated have targeted an

individual facet of the injury. It is now recognized that TBI is a very heterogeneous type of

injury that varies widely in its etiology, clinical presentation, severity and pathophysiology. The
Journal of Neurotrauma

pathophysiological sequelae of TBI are mediated by an interaction of acute and delayed

molecular, cellular and physiological events that are both complex and multifaceted 2.

Accordingly, a successful TBI treatment may have to simultaneously attenuate many injury

factors.

We postulate that nutritional approaches are set to meet this need, playing an important role in

future management options for mild-to-moderate TBI, and hence this contribution reviews

recently published data describing nutrition-related recommendations for patients with mild or

moderate TBI 3;4, suggesting that targeted nutrient therapy may promote functional recovery

following TBI. Although the benefits of nutritional support in critical illness are widely accepted

and supported by objective reviews of the evidence, the limited provision of nutritional support

to neurotrauma patients was recently documented to be suboptimal 5;6. To convince more

clinicians to provide enhanced nutritional support to neurotrauma patients, better evidence may
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be needed, as critically ill patients admitted with TBI are believed to be at the highest risk of

delayed gastric emptying 7 and feed intolerance (prevalence of up to 80 %; 3;5). Although the

current Brain Trauma Foundation Guidelines do not make a definitive statement on specific

nutritional formulations to improve the outcome of mild-to-moderate TBI patients, they do

recommend that patients with severe TBI receive their goal nutrition support by at least day 7 of

injury 8. There are also data indicating that morbidity and mortality are decreased in patients

receiving early feeding compared with those given standard nutritional treatment 9-11. However,
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

the evidence is still not strong enough to establish a standard 3;12;13, and evidence is lacking for

the postacute rehabilitation period.


Journal of Neurotrauma

Intervention studies conducted using four different nutrients, namely omega-3, zinc, vitamin D

and glutamine, will be reviewed. Understanding that nutrients will not be the sole treatment for

TBI, and that it is a potentially powerful adjunct to promote neuro-repair, the four diet

components reviewed were selected based on our review of the effectiveness of all the IOM-

recommended diet components as monotherapies, targeted to a single factor/pathway 6. The

2011 IOM report also includes recommendations for using antioxidants, BCAA, choline,

creatine, magnesium, and polyphenols. As most drugs aimed at select pathways of injury have

achieved little, if any, success in larger clinical trials, treatments with broader, pleiotropic effects

need to be explored. We concur with Loane 14, that mild TBI, with its intrinsic heterogeneity,

may require multi-potential approaches to target multiple components of the secondary TBI

injury cascade. Finally, we also considered uptake as the four diet components reviewed can

be readily taken up by the brain, and can be orally administered in addition to the parenteral

route. Due to the complex and multi-factorial nature of TBI, we contend that a combination of
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putative beneficial dietary components would simultaneously act on multiple disease processes

to effectively treat the neuroinflammation associated with mild-to-moderate TBI. Major

deficiencies are highlighted, and possible dietary supplementation solutions are presented.
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)
Journal of Neurotrauma
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OMEGA-3: n-3 polyunsaturated fatty acids (PUFAs) are important structural components of cell

membranes, modulating membrane fluidity, cell wall thickness, cell signaling, and mitochondrial

function 15;16. Long-chain n-3 PUFAs, including eicosapentaenoic acid (EPA, 20:5 n-3) and

docosahexaenoic acid (DHA, 22:6 n-3), are highly enriched in neuronal synaptosomal plasma

membranes and vesicles 15. DHA, the predominant PUFA in the central nervous system (CNS),

is readily retained in neuronal plasma membranes. In turn, neuronal DHA influences the

phospholipid content of the plasma membrane by increasing production of phosphatidylserine


Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

and phosphatidylethanolamine, and by promoting neurite outgrowth during development and

adulthood 17;18. However, in the modern Western diet, the principal dietary PUFA is not DHA,

but alpha-linolenic acid (ALA, 18:3 n-3), which is obtained through ingestion of certain nuts and
Journal of Neurotrauma

vegetable oils. The efficiency of the conversion of ALA to EPA, however, is much lower than

the absorption of EPA from food containing it. Because EPA is also a precursor to DHA,

ensuring a sufficient level of EPA on a diet containing neither EPA nor DHA is harder both

because of the extra metabolic work required to synthesize EPA and because of the use of EPA

to metabolize into DHA 19. EPA and DHA give rise to resolvins, and DHA is also a precursor

for protectins (e.g. NPD1), both of which are potently neurotherapeutic and neuroprotective 20.

Therefore, increased ingestion of dietary sources rich in EPA and DHA, such as cold-water fish

species and fish oil, may help improve a multitude of neuronal functions, including long-term

potentiation and cognition 21;22.

It is estimated that human beings evolved consuming a diet containing approximately equal

amounts of n-6 and n-3 PUFAs (n-6:n-3 ratio of 1-2:1) 23;24. In contrast, the present-day Western

diet is relatively deficient in n-3 PUFAs and very high in n-6 PUFAs (n-6:n-3 ratio of 10-20:1).
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Factors contributing to this shift include the increase in red meat consumption, decrease in fish

consumption, and the industrial production of animal feeds rich in n-6 PUFAs, resulting in red

meat rich in n-6 and poor in n-3 PUFAs. The same pattern is true for farm-grown fish, chicken

meat and eggs, which along with consumption of ALA-enriched vegetable oils, further

contributes to the present-day imbalance of n-6:n-3 23;24. The current Western diet is high in

vegetable-derived, cholesterol lowering fatty acids as a result of the indiscriminate

recommendation in 1988 to substitute animal fats for vegetable fats, aimed at lowering serum
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

cholesterol concentrations 25. The net effect of these changes has led to an increase in the

consumption of vegetable oils relatively high in n-6 fatty acids [for example, corn, cotton,

peanut, soybean, sunflower, and safflower oils], instead of vegetable oils high in n-3 fatty acids
Journal of Neurotrauma

[including canola, flaxseed and linseed oils]. Hence, the increased n-6/n-3 ratio, and most

importantly, the CDC now estimates that up to 80% of the United States population is omega-3

fatty acid deficient. This shift can cause serious long-term health effects as the PUFA

composition of cells involved in inflammatory responses (e.g. macrophages, neutrophils,

monocytes, lymphocytes) and microglia in the brain vary in response to the dietary source.

Specifically, the DHA content and the resultant ratios of proinflammatory eicosanoids (e.g.

prostaglandins, thromboxanes, and leukotrienes) and neuroprotective docosanoids (e.g. NPD1)

are directly impacted by diet 26;27. The question is how increased DHA levels can benefit the

TBI brain. It is well known that TBI causes degradation of membrane phospholipids 28, resulting

in disturbances in cellular membrane functions, and contributing to secondary neuronal injury 29.

Recently, Wu and colleagues provided evidence that DHA supplementation increases DHA

content in the brains of TBI rats, which may help preserve membrane fluidity and integrity and

enhance cognitive function 30. In animal models of TBI, decreased levels of -amyloid precursor
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protein, a marker of axonal injury, were observed after 1 month of dietary supplementation with

DHA 31;32, and decreased axonal injury counts and apoptotic markers as well as improved

memory have also been documented in rats with TBI when given prophylactic DHA for 30 days
33
. Synaptic membrane phospholipids are preferentially enriched in n-3 fatty acids, especially

DHA. Thus, increased dietary DHA content may help prevent the loss of DHA from membrane

lipids, and thus reduce the oxidative damage to the plasma membrane. Hence the findings from

Wu and colleagues in rats 30, suggest that DHA-induced effects could influence the relative
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

vulnerability or resilience of an adult to TBI (see Table 1), but translation studies are needed.

This is a critical and timely concern as recent reports identified a very low n-3 PUFA status

among active duty U.S. military and has linked this nutritional deficiency to reduced cognitive

performance and heightened neuropsychiatric disorders and suicide risk 34-36. Similar
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epidemiological comparisons have linked relative consumption of n-6 and n-3 PUFAs to

cardiovascular and autoimmune disease 37;38. Such diet-derived vulnerabilities, which we

hypothesize will extend to TBI, should be readily and safely correctible, so the results of this

research are highly translatable. n-3 PUFA dietary supplements can be directly incorporated into

the regular Western diet as prophylactic agents, given following mild-to-moderate TBI, and

included in enteral feeding formulations for severe TBI victims.

Multiple preclinical studies have suggested that DHA and/or EPA supplementation may have

potential neuroprotective benefits through a multitude of diverse, but complementary

mechanisms 31-33;39;40. Preclinical studies reveal DHA to be a pleiotropic molecule with

neuroprotective effects which involve inhibition of proinflammatory transcription factors (NF-

B), repression of pro-apoptotic proteins (Bax), activation of anti-apoptotic proteins (Bcl-2),


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activation of neurotrophins (BDNF), reduction in excitotoxicity, inhibition of inflammatory

gene expression, suppression of oxidative reactions, modulation of calcium and potassium

channels, and suppression of amyloidogenesis 15;41-43. However, key issues influencing efficacy

such as optimal timing, dosing, and the interplay among underlying neurobiological

mechanism(s) are undefined; thus, n-3 PUFA use in most medical facilities is often arbitrary.

Studies utilizing rodent models of experimental injury have shown that pre-injury dietary

supplementation with fish oil effectively reduces post-traumatic elevations in protein oxidation,
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

resulting in stabilization of multiple molecular mediators of learning, memory, cellular energy

homeostasis and mitochondrial calcium homeostasis, and improvements in cognitive

performance 39;40. The benefits of pre-injury DHA supplementation have been independently

confirmed 32, and DHA administered following TBI has been shown to significantly reduce the
Journal of Neurotrauma

number of swollen, disconnected and injured axons 31;33. Of note, DHA has also provided

neuroprotection in experimental models of both focal and diffuse TBI 31-33;39;40. Studies in other

neurotrauma models have revealed a variety of potential mechanisms for the neuroprotective

effects of DHA, including the restoration of brain homeostasis following TBI 17;18;39;40;44-47.

Despite abundant laboratory evidence supporting its neuroprotective effects in experimental

models, the role of dietary DHA and/or EPA supplementation in human neurological diseases

remains uncertain. To date, there have been no clinical trials investigating the effects of DHA

and/or EPA dietary supplementation on the treatment or prevention of the deleterious effects of

TBI. Several population-based, observational studies have suggested that increased dietary fish

and/or n-3 PUFA consumption may reduce risk for ischemic stroke 48;49, and randomized control

trials (RCTs) have also demonstrated significant reductions in ischemic stroke recurrence 50, and
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reduced incidence of both symptomatic vasospasm and mortality following subarachnoid

hemorrhage 51. A few studies, on the other hand, have found no statistically significant

affirmation of neurological impairment following ischemic stroke 52 or reductions in epileptic

seizure frequency 53;54. Thus, the clinical evidence thus far appears equivocal. However, the

overall difficulty in controlling for basal dietary intake of PUFAs between experimental groups,

lack of good study design and the significant heterogeneity of the studied patient populations

makes all of these studies difficult to interpret. Nonetheless, the multi-mechanistic


Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

neuroprotective properties and the positive preclinical findings associated with n-3 PUFA-

supplementation warrant well designed clinical trials to determine whether supplementation may

improve outcomes following mild-to-moderate TBI.


Journal of Neurotrauma

Recommendations for OMEGA-3: Being an essential part of the human diet, omega-3s are

highly safe and well tolerated 55;56. While omega-3s are readily taken up by the brain, and they

can be orally administered in addition to the parenteral route 57;58, documentation of the factors

determining optimal use is crucial. For example, the Institute of Medicine (IOM) notes that

when taken orally, the effects of n-3 fatty acids are not evident for days to weeks because of their

slow incorporation into cellular membranes 6. Hence, initiation of oral administration following

TBI therefore may not be of immediate benefit. The U.S. Food and Drug Administration has

confirmed the overall safety of fish oil both DHA and EPA at levels up to 3.0 g/day are

generally recognized as safe 59, while the American Heart Association has furthermore

established intakes of 1.0 g of EPA and DHA from fish or fish oils for patients with

cardiovascular disease, and supplements of 24 g for subjects with high blood triglycerides 60.

Most clinical studies of DHA have employed a dose of 26 g/day, and no consistent adverse
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events have been observed in humans consuming from less than 1.0, up to 7.5g/day of DHA 61.

Potential harmful effects of n-3 PUFAs, however, have been described in the literature. Due to

the established anti-thrombotic action of these compounds, for instance, they may increase the

risk of hemorrhagic stroke, as suggested by a necropsy-based study of four cases in Greenland 62.

Multiple clinical trials have shown that high-dose fish oil consumption is safe, even in patients

receiving other agents that may increase the risk of bleeding, such as aspirin and warfarin 63-65.

The overall clinical data suggests that DHA at doses up to 6 g/day does not have deleterious
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

effects on platelet aggregation or other clotting parameters in normal individuals, and fish oil

does not augment aspirin-induced inhibition of blood clotting 61. Platelet function is, on the

other hand, inhibited by DHA consumption in type 2 diabetics, but it is suggested that this may
Journal of Neurotrauma

actually be of benefit to these individuals, especially when coupled with the other activities of

DHA 66. Nevertheless, it may be prudent to discontinue high-dose supplementation in the setting

of a TBI patient presenting with poly-trauma (e.g. an acute bleeding illness or at high risk for

hemorrhagic stroke) or, as is frequently recommended with aspirin, warfarin, and clopidogrel,

prior to planned invasive procedures with the highest risk for bleeding complications 67-70. While

clinical studies thus far have not yet identified an effective omega-3 treatment strategy against

secondary injury after traumatic insult to the brain has occurred 71, a recent, three-patient case

report involved the Neuroceutical Augmentation for TBI (NATBI) protocol, using 2g of

omega-3/day to successfully treat three severe cases of TBI 72. Each 1-gram capsule (Loveza,

GSK) contained 38% DHA, 47% EPA, and 17% other fish oils in the form of the ethyl ester.
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ZINC: Zinc (Zn) is a life-sustaining trace element with structural, catalytic, and regulatory roles

in neurobiology, and is required for normal mammalian brain development and physiology.

Deficiency or excess of Zn contributes to alterations in behavior, abnormal CNS development,

and neurological disease 73. In this light, it is not surprising that dietary Zn reportedly also shows

both neurotherapeutic and neuroprotective roles in treating the underlying immune-excitotoxicity

that occurs with mild-to-moderate TBI (see Table 1).


Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

TBI victims reportedly exhibit significantly depressed serum Zn levels as well as increased

urinary Zn excretion 74. Moreover, urinary Zn excretion was proportional to the severity of the

brain injury, and mean urinary Zn levels were 14 times greater than normal values in the most
Journal of Neurotrauma

severely injured patients. It has also been observed that patients with severe head injuries

develop hypoalbuminemia and inflammation 75;76. Because albumin is the major serum transport

protein for Zn, hypoalbuminemia would potentially impair both Zn transport and availability.

Induction of cytokines such as interleukin-1 during the acute phase response may further

compromise Zn availability and reduce Zn stores due to downregulation of genes of the

proinflammatry cytokines including IL-1, IL-6 and TNF-, suggesting that a good intracellular

Zn homeostasis may reduce neuroinflammation or, at least, may better keep under control the

inflammatory status 77. Given the apparent role of TBI in compromising Zn status, Young and

colleagues 78 tested the effectiveness of using intravenous Zn supplementation in 68 patients

following TBI to offset Zn losses and maintain protein balance in an attempt to improve

neurological outcomes. Zn supplementation resulted in increased levels of serum pre-albumin

and retinol-binding protein, suggesting improved visceral protein synthesis in TBI patients. Two

weeks after injury, patients in the Zn-supplemented group had better Glasgow Coma Scale
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(GCS) scores than control patients given adequate Zn, and improvements were maintained at 21

and 28 days. Interestingly, the differences between the groups were seen despite the fact that

neither serum Zn concentrations nor Zn levels in cerebral spinal fluid were changed by Zn

supplementation, suggesting that the Zn is taken up into tissues after administration, and

illustrating the fact that serum Zn levels are not a good indicator of Zn status 79.

As many as 40 % of patients hospitalized with TBI develop major depression, making it the most
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

common long-term complication of TBI 80, and depression is associated with a lower

concentration of Zn in peripheral blood 81. Involvement of Zn in antidepressant therapy, which

was indicated by animal experiments, has some clinical correlates. Multiple groups report that

human depression might be accompanied with lower serum Zn concentrations 82-84. These
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findings were confirmed by Maes 85, who found that the subjects suffering from major

depression showed significantly lower serum Zn levels than non-depressed controls.

Interestingly, they also observed that the patients with minor depression showed intermediate Zn

levels. Moreover, the unipolar depression was not only associated with lower blood Zn levels,

but the severity of the illness [expressed according to Hamilton Depression Rating Scale

(HDRS)] was negatively correlated with serum level of this ion 85;86. The findings that the

lowered serum Zn concentrations may be normalized after successful antidepressant therapy 87;88

further support the notion that serum Zn concentrations are a sensitive and specific marker of

depression. A recent systematic review of four RCTs on the efficacy of Zn supplementation for

reducing, or preventing depressive symptoms suggests potential benefits of Zn supplementation

as a stand-alone intervention or as an adjunct to conventional antidepressant drug therapy for

depression 89. Although there are no data on the use of supplemental Zn to reduce or prevent
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depressive symptoms in patients with TBI-associated depression, the use of Zn to improve mood

may be effective among this patient population.

Experimental evidence indicating a possible role for the use of Zn as a treatment in TBI was

obtained using a rodent model to test the hypothesis that Zn supplementation before injury could

increase resilience and improve brain-injury outcomes 90. A controlled cortical injury (CCI)

model of TBI in adult rats induced anhedonia, a depression-like symptom in the rat, and although
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

this symptom was observed in injured animals fed a diet with adequate Zn (30 ppm, or 15 mg/d),

four weeks of Zn supplementation (180 ppm, or 90 mg/d) before the injury prevented the

appearance of anhedonia following TBI. CCI also produced anxiety-like behaviors; however,
Journal of Neurotrauma

animals fed the Zn-supplemented diet prior to injury appeared to have greater resilience to

injury-induced anxiety. This study also examined whether Zn supplementation could prevent

TBI-associated losses in spatial learning and memory, and while CCI resulted in significant

performance deficits on the Morris Water Maze test, rats that were fed the Zn-supplemented diet

prior to TBI showed no differences from sham-operated control rats suggesting that Zn

supplementation may improve cognitive resilience to TBI 90.

A concern for nutritionists arises from reports that high concentrations of free Zn are neurotoxic.

Specifically, the accumulation of free Zn following TBI in animal models appears linked to

neuronal injury 91;92. In brief, the free Zn, sequestered in synaptic vesicles, is released from

neurons into the synaptic cleft where it results in postsynaptic neuronal death 93. Although the

release of synaptic Zn after injury is well accepted in the field, there have been indicators that

other pools of free Zn may contribute to neuronal damage after injury. For example, using an in-
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vitro model of ischemic brain injury in which cells were exposed to 3h of oxygen-glucose

deprivation (OGD) followed by incubation under normal conditions, free Zn levels were

quantified with radiometric mitochondrial and cytoplasmic Zn sensors. Mitochondrial free Zn

levels 1h after OGD increased to 10pmol/l from 0.2pmol/l at control levels, whereas at the same

time cytosolic free Zn concentrations were decreased significantly. Mitochondrial free Zn

eventually tapered off to normal physiological levels by 2h after OGD, whereas cytosolic free Zn

gradually increased by about 10-fold, 24h after OGD 94. This work suggests that changes in the
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

subcellular localization of free Zn following neuronal injury are complex and are likely to have a

significant impact on neuronal survival. The data provide further evidence that disruption of Zn

homeostasis during a brain injury can be detrimental to the survival and viability of neurons. It
Journal of Neurotrauma

is worth noting that investigations are ongoing to develop clinically relevant treatments to

prevent Zn-mediated neuronal death. A 3h pretreatment of mouse hippocampal primary neurons

with urokinase plasminogen activator (uPA), a serine protease that converts plasminogen to

active plasmin, inhibited Zn-induced cell death. Thus, future work should be conducted to

determine the extent to which uPA can be utilized as a potential treatment and neuroprotective

agent in Zn-induced cellular and neuronal damage 95. In addition to affecting the site of injury,

TBI produced either by fluid percussion injury 91 or mechanical cortical trauma 96 resulted in

neuronal death in the dentate gyrus, hilus, and CA1 regions of the hippocampus. The neuronal

injury appears to be associated with presynaptic Zn release 97, and the cell death was largely

prevented by treatment with the Zn chelator calcium disodium EDTA 91;98, hence the suggestion

that Zn in high concentrations following TBI is neurotoxic. These dual neurotoxic and

neuroprotective effects of Zn are widely known 99, but the precise mechanisms responsible for its

neurotoxic and neuroprotective effects remain unclear.


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TBI induces a variety of damaging oxidative processes, and a number of studies show a role for

Zn deficiency in the induction of reactive oxygen species (ROS). An understanding of the

possible role of free Zn in neuronal death raises the question of whether clinicians should be

treating brain-injured patients with supplemental Zn, particularly in acute periods after severe

injury when the blood-brain barrier that regulates brain Zn uptake has been disrupted. Using an

animal model of TBI, Yeiser 100 reported that 4 weeks of dietary Zn supplementation (180 ppm,
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

or 90 mg/d) following TBI did not significantly increase cell death (as measured by TUNEL

labeling) in any cell type examined, including microglia, macrophages, neurons, or

oligodendrocytes at the site of injury or any other region of the CNS. These data suggest that
Journal of Neurotrauma

concern about the potential neurotoxicity of enteral Zn supplementation in TBI patients is

unwarranted. Reports that intraperitoneal injections of Zn significantly increased the infarct size

and impaired motor behavior after focal ischemia in rats suggest, however, that caution is

warranted when using Zn parenterally in moderate-to-severely injured patients 99;101.

Recommendations for Zn Available clinical evidence suggests that in the acute care situation

following TBI, Zn deficiency should be prevented to maintain visceral protein stores and to

optimize the potential for neurological recovery. In patients with a moderate-to-severe brain

injury, there are acute increases in urinary Zn excretion and significant decreases in serum Zn

levels that have been shown to be proportional to the severity of injury 74. The only dose of

supplemental Zn that has been tested in a clinical setting is 12 mg Zn-sulphate/day administered

intravenously for the first 15 days after injury. After day 15, an oral dose of 22 mg/day was

provided 78. Zn supplementation was associated with increased visceral proteins such as
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prealbumin and retinal-binding protein, and improvements in GCS scores were seen 2 weeks

after the start of treatment 78. However, there have been no clinical trials to assess the efficacy of

Zn as a treatment for mild TBI. With the Tolerable Upper Intake Level (UL) set at 40 mg/day
102
, these doses are not likely to have adverse effects. However, the impact of parenteral

administration of Zn has not been independently investigated, nor has it been compared to

enteral feeding in a TBI model. The data does suggest that recommendations to supplement Zn

for the treatment of mild-to-moderate TBI should include cautionary advice not to chronically
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

exceed the UL for Zn intake. Considering the paucity of clinical trials, the data strongly suggest

that Zn status should be monitored and maintained after a brain injury, not only because of the

reported neurocognitive outcomes, but also because both Zn deficiency and TBI have been

associated with oxidative stress 103;104.


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VITAMIN D: A fat-soluble vitamin that is essential for maintaining normal calcium

metabolism, vitamin D is found in some foods including fish and egg yolks. Fortified foods such

as milk and cereals provide most of the vitamin D in American diets. Vitamin D can also be

manufactured in skin upon exposure to ultraviolet B rays from sunlight. Vitamin D is required to

promote normal brain development, maintain pregnancy, and for skeletal development.

However, the vitamin D obtained from sun exposure, food, and supplements is biologically inert

and must undergo two hydroxylations in the body for activation. The first occurs in the liver and
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second

occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D

[1,25(OH)2D], also known as calcitriol 105;106.


Journal of Neurotrauma

Vitamin D deficiency is defined as serum 1,25(OH)2D of less than 30 nmol/L 106. A recent

global review of vitamin D status has shown that its intake is often too low to sustain healthy

circulating 1,25-dihydroxyvitamin D 105. Approximately one billion people worldwide are

estimated to be vitamin D deficient with people living in Europe, the Middle East, China and

Japan at particular risk 107;108, but vitamin D deficiency has become epidemic for all age groups

in the United States and Europe 109;110. Vitamin D deficiency has been associated with

inflammatory, autoimmune, cardiovascular, neuromuscular, and neurodegenerative diseases, as

well as cancer 109, and population based studies suggest that vitamin D deficiency is associated

with an increased prevalence of Parkinson's disease 111, dementia, Alzheimer's disease, and

increased stroke risk in the elderly 112-114. Deficiency is more common in women than men (9.2

% vs. 6.6 %) and pregnancy is known to represent a particularly high-risk situation 115.
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Vitamin D deficiency may increase inflammatory damage and behavioral impairment following

experimental injury and attenuate the protective effects of post-traumatic progesterone treatment
116
. There have been no clinical trials to assess the efficacy of vitamin D as a treatment for mild

TBI, but the studies by Buell 112 and Witham 117 using stroke victims are informative: Vitamin D

insufficiency (serum levels between 10-20 ng/ml) was associated with twice the risk of stroke.

These authors conclude that vitamin D insufficiency and deficiency is associated with all-cause

dementia, Alzheimer disease, stroke (with and without dementia symptoms), and MRI indicators
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

of cerebrovascular disease. These findings suggest potential neuroprotective and/or vasculo-

protective roles for vitamin D that might have relevance to mild TBI (see Table 1). More recent

research has suggested that vitamin D supplementation and the prevention of vitamin D
Journal of Neurotrauma

deficiency may serve valuable roles in the treatment of TBI as a neuroprotective adjuvant for

post-TBI progesterone therapy 109;116;118. Progesterone is one of the few agents to demonstrate

significant reductions in mortality following TBI in human patients 119;120, and in vitro and in

vivo studies have suggested that vitamin D supplementation with progesterone administration

may significantly enhance neuroprotection 118;121. Both agents have high safety profiles, act on

many different injury and pathological mechanisms, and are clinically relevant, easy to

administer, and inexpensive. While there are two Phase III clinical trials underway evaluating

the efficacy of intravenous progesterone for moderate-to-severe TBI 119;122, there is currently

only one pilot study evaluating progesterone for the treatment of concussion/mild TBI (see

www.clinicaltrials.gov). Our perspective is that the combination of progesterone and vitamin D

should be considered in pre-clinical and clinical studies as a novel and compelling approach to

TBI treatment.
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Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for

the non-specialist to select the most suitable for the individual patient. Available drugs with

vitamin D-like activity are not all the same either in terms of pharmacological actions, and/or

side-effects. They have specific characteristics that may be useful to know in order to operate

the best choice in the individual TBI-patient. Natural vitamin D products are those identical to

natural metabolites, while the most frequently used vitamin D supplements are synthetic

molecules (i.e. bioengineered molecules not found in nature), which are generally referred to as
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

"analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with

normal renal function to correct vitamin D-deficiency and improve, respectively, age- or growth-

related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more
Journal of Neurotrauma

rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must

be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin

D, has the most potent hypercalcemic effect in both normal and renal failure patients. Calcitriol

is best used in cognitive dysfunction, including dementia resulting from TBI 123. Importantly,

reno-protective and cardio-protective effects of these analogs have been recently evaluated by

means of RCTs in renal patients with partially positive renal effects and negative cardiac results

but no similar studies have been conducted in the TBI population.

Recommendations for vitamin D Schnieders 124 recently reported that 65% of patients with

varying degrees of TBI were vitamin D deficient i.e. having serum 25-OHD level < 30 nmol/L

(using the Endocrine Society guidelines). Thus a vitamin D deficiency, combined with an

omega-3 deficiency, may work synergistically to worsen outcome in patients with TBI. As both

are very prevalent in the U.S. population, and even more pronounced in critically ill patients with
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TBI, at-risk patients should be routinely supplemented with vitamin D and omega-3, in our

opinion.

The Food and Nutrition Board recommends that generally healthy adults take 600 IU (15 g) of

vitamin D daily 106, and conservatively set a tolerable upper intake level (UL) of 4,000 IU/day

(100 g) for all adults. While rapid correction of serum 25-OHD levels can be easily achieved

with oral administration of high-dose cholecalciferol, most multivitamins contain 400 IU of


Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

vitamin D, and single ingredient vitamin D supplements are available for additional

supplementation. The Vitamin D Council suggests that a serum level of 50 nmol/L is the ideal,

and to achieve this, it is recommended that adults should take 8001000 IU of vitamin D/day

from dietary and supplemental sources 125-127, when sunlight is unable to provide it. Specific
Journal of Neurotrauma

amounts of vitamin D are detailed in a recent clinical trial 128 that reported on using the

combination of vitamin D (8.0 g/L) and/or progesterone (6.3 g/L) for treating patients with

severe TBI (GCS <8). Within 8 hours of the neurotrauma incident, patients were injected with 1

mg/kg of progesterone intramuscularly every 12 hours for 5 days, and/or 5 g/kg vitamin D

once-a-day for 5 days. In this study, significantly greater improvements in patient outcomes (as

measured by GCS improvement), occurred in the group receiving combination therapy, versus

either of the mono-therapy groups.

While pharmacological doses have been utilized in severe cases of TBI (the Neuroceutical

Augmentation for TBI protocol 72 uses a regime that includes 50,000 IU/day of vitamin D3),

there has been little toxicity reported in adults taking doses of vitamin D as high as 10,000

IU/day, although toxicity becomes generally present at 20,000 IU/day 129. Finally, the required
Journal of Neurotrauma
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

(IU) = 40 X (50 - serum 25-OHD3) X body weight, measured in kg 130.


and body weight. For example, to reach the serum 25-OHD3 target level of 50 nmol/l, the dose
loading dose for cholecalciferol can be calculated on the basis of the actual serum 25-OHD3 level
22
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GLUTAMINE: A non-essential amino acid, glutamine (Gln) is widely distributed throughout

the body, and can act as an essential amino acid in certain clinical settings. Over the past three

decades, Gln studies have been conducted in disorders that are characteristic of significant

metabolic stress, including post-surgical, septic, critically ill and multiple-trauma patients, in

which the trophic actions of Gln on rapidly dividing cells (lymphocytes, mast cells and

enterocytes) could have beneficial effects 131;132. Gln requirements of the gut are increased in

burn injury, major surgery and sepsis, and a lack of Gln promotes mucosal atrophy, an increase
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

in intestinal permeability and bacterial translocation, and a reduced synthesis of glutathione,

which is an important factor for antioxidant defense 133;134. Several clinical and experimental

studies have demonstrated that Gln had a specific inhibitory effect on production of pro-

inflammatory cytokines in human gut 135, attenuated systemic inflammatory response in early
Journal of Neurotrauma

post-operative patients 136, attenuated leucocyte-endothelial cell adhesion, and reduced

macroscopic and microcirculatory inflammatory activity in indomethacin-induced intestinal

inflammation 137.

In human brain injury studies, Gln-enriched enteral diets have been provided to patients with

moderate-to-severe TBI, either individually at 0.5 g/kg/day 138, with probiotics 139, or with

alanine 140. The results demonstrate that Gln administration following more severe TBI shortens

hospital stays, prevents loss of lean tissue, and decreases infection rate, suggesting that Gln-

enriched enteral feeding could also improve the nutrition status, and accelerate the recovery of

patients with mild-to-moderate TBI. The criteria for including Gln as a recommended

nutrient for mild-to-moderate TBI stems from the reports of TBI-induced pathophysiological

changes that include intestinal inflammation and mucosal apoptosis following TBI 141, and that
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Gln improved intestinal function in animal models of TBI 142;143. These animal studies suggest

that Gln modulates TBI-induced intestinal pathophysiological changes, possibly providing a

therapeutic intervention to maintain and improve intestinal function in TBI patients.

Two RCTs reported on the benefits of Gln supplementation in critically ill patients when the

patients presented with a low baseline Gln level (plasma levels <420 mol/L) 144;145, however the

patients with a normal plasma Gln level did not benefit from the same supplementation. Rodas
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

146
reported that elevated baseline levels of plasma Gln (>930 mol/L) in critically ill patients

was actually associated with increased mortality. A meta-analysis by Chen 147 showed that Gln

supplementation at doses higher than 0.5 g/kg/day increased mortality in ICU patients, while
Journal of Neurotrauma

ICU patients benefitted when the Gln dose was between 0.3-0.5 g/kg/day. The recent RCT

reported by Heyland 148 examined Gln and antioxidant supplementation in 1,223 critically ill

patients (average age 63yr, with two or more organ failures), and concluded that Gln was

associated with an INCREASE in mortality among critically ill patients, the treatment was above

what could be obtained through any diet the RCT intervention required an intravenous dose of

approx. 65g/day, continuously for 28 days. In a follow-up, these same authors 149 state that their

high-dose Gln regime appeared to cause harm. It is, therefore, critical to choose an optimal

dose of Gln, given the discrepancy among different studies, and the knowledge that high dosage

Gln supplementation may be harmful 149.

Recommendations for Gln administration While lower plasma Gln levels have been associated

with a higher mortality rate in critically ill patients 150, critical illness is not necessarily

associated with a low plasma Gln 151. Healthy subjects have an endogenous Gln production of
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50-80 g/day 152;153, and most of the de novo Gln synthesis takes place in skeletal muscle

thereafter it is exported to the splanchnic area to be used mostly in enterocytes and immune cells
132
. In the critically ill patient, Gln production is insufficient to maintain plasma concentrations
153;154
, and intravenous Gln supplementation of 0.3-0.5 g/kg/day provides an improved outcome

for patients on TPN 131;138;155;156, and/or when patients present with a low plasma Gln at baseline

(<420 mol/L). However, most subjects with mild, or mild-to-moderate TBI, do not require

TPN hence, an exogenous Gln supplementation of 20-30 g/day is expected to normalize the
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

plasma Gln concentration 157. We are not advocating for pharmacological doses of Gln, as

manipulation of the amino acid composition of the diet by grossly distorting the balance (such

that Gln constitutes more than 50% of total dietary protein as seen in the RCT by Heyland 148),
Journal of Neurotrauma

may have adverse clinical consequences, including the potential for toxicity. The Nutrition

Support Therapy Guidelines recently published by the Society of Critical Care Medicine

(SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN) recommend the

use of immune-modulating enteral formulas, including Gln, in trauma patients. The

Guidelines caution the use of formulations containing arginine in patients with severe sepsis,

but TBI is not discussed 158-160. Further Guidelines recommendations support the addition of

enteral Gln to standard non-Gln supplemented enteral formulas for trauma patients standard

dosing of Gln powder mixed with water should provide 0.3-0.5 g/kg/d and be given in two or

three divided doses (approx. 22-38g/day), via a feeding tube 159. As the clinical data suggests

that for Gln, the administration route, dose, timing, and phase/severity of TBI probably all affect

outcome(s), our contention that lower, physiological doses of Gln produce very favorable

outcomes in the gut (i.e. repair/reduction of leakage) is supported by i) a recent study that

provided a lower oral dose (approx. 53g Gln/day) for just 7-days to prevent exercise-induced
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gastrointestinal leakage in healthy, young subjects (average age 25yr) 161, and ii) the

Neuroceutical Augmentation for TBI (NATBI) protocol that uses a combination of vitamin D3,

progesterone, omega-3, and enteral Gln (20g/daily) to treat severe cases of TBI 72. A resolution

would be to determine plasma Gln levels before giving Gln to patients with mild-to-moderate

TBI.
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)
Journal of Neurotrauma
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SUMMARY AND CONCLUSIONS It is almost a certainty that any single future intervention

will be insufficient to address the multitude of physical, behavioral and cognitive problems

caused by TBI. Because of the complex and multi-factorial nature of the TBI disease process,

we posit that a mixture of putative beneficial dietary components would simultaneously act on

multiple disease processes associated with mild TBI, and thereby may constitute an effective

nutrition-based strategy for reducing both the cognitive and behavioral deficits associated with

mild-to-moderate TBI. The evidence supporting multiple dietary components to reduce TBI-
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

associated neuroinflammation is strong, and the transition from conducting research to

formulating policy is being facilitated by the low cost of these recommended food combinations.

As all these food products demonstrate neuroprotective and neurotherapeutic benefits, there may
Journal of Neurotrauma

be considerable essential synergism between them for affecting the underlying immune-

excitotoxicity that occurs with mild TBI.

The recent IOM report 6 recommends that evidenced-based guidelines include the provision of

early (within 24h of injury) nutrition (more than 50% of total energy expenditure and 1-1.5 g/kg

protein) for the first two weeks after the injury. Although the Brain Trauma Foundation has

recommended achieving full caloric replacement by day 7 following TBI, and guidelines for

nutritional support in head injury that discuss dosage, administration route, and timing for

moderate-to-severe TBI have been reviewed elsewhere 5;13;162; no agreement has been reached

[see Cook 3]. Clearly, further study is required to assess the combined effects of these foods on

cognitive and behavioral recovery following mild TBI, but there appear to be no downsides to

any of these food agents, when used appropriately. The major challenges of the future are

performing well designed clinical studies in patients to confirm anticipated effects, to define the
Journal of Neurotrauma
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)
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effects.
optimal doses, to compare single vs. multiple dietary components, and to assess possible side-
28
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Acknowledgements: AGS and MLC wrote the paper; AGS had primary responsibility for final

content. Both authors read and approved the final manuscript.

Disclosure statement: The opinions or assertions contained herein are the private views of the

authors and are not to be construed as official or as reflecting the views of the U.S. Army or the

Department of Defense. Any citations of commercial organizations and trade names in this

report do not constitute an official Department of the Army endorsement of approval of the
Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

products or services of these organizations. No competing financial interests exist.


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Table 1. Plausible mechanisms of action by selected nutrients and food components that might

affect TBI outcomes.

Cell Processes n-3 PUFA Glutamine Vitamin D Zinc

Apoptosis (programmed cell death) X X X X

Autolysis (self-digestion) X

Autophagy (process of cell degradation) X X X X


Nutritional treatment for traumatic brain injury (doi: 10.1089/neu.2013.3234)

Decreased ATP/Mitochondrial Dysfunction X X X X

Edema X X

Excitotoxicity X X X

Neurogenesis (generation of new neurons) X X X


Journal of Neurotrauma

Neuroinflammation X X X X

Neuroplasticity (changes in neural X X X


pathways/synapses)
Neurotrophic factors X X

Oxidative Stress X X X X

Synapses X X

LEGEND: The four nutrients/food components listed here act on multiple and diverse processes

that are common to brain injury, and therefore their effects (beneficial and adverse) should be

considered.