8
Branched-Chain Amino Acids

The branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) are nutritionally essential in that they cannot be synthesized endogenously by humans and must be supplied by diet. They differ from other essential amino acids in that the liver lacks the enzymes necessary for their catabolism.

In addition to their function as structural components of proteins, BCAAs also seem to exert regulatory control of protein metabolism. In rodent tissue in vitro, increased concentrations of BCAAs stimulate protein synthesis and inhibit protein catabolism, whereas other amino acid mixtures lacking BCAAs have no such influence. In humans, BCAAs inhibit protein catabolism, but have little effect on synthesis (see Matthews, 2005, for review).

BRANCHED-CHAIN AMINO ACIDS AND THE BRAIN

In the brain, BCAAs have two important influences on the production of neurotransmitters. As nitrogen donors, they contribute to the synthesis of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) (Yudkoff et al., 2005). They also compete for transport across the blood-brain barrier (BBB) with tryptophan (the precursor to serotonin), as well as tyrosine and phenylalanine (precursors for catecholamines) (Fernstrom, 2005). Ingestion of BCAAs therefore causes rapid elevation of the plasma concentrations and increases uptake of BCAAs to the brain, but diminishes tryptophan, tyrosine, and phenylalanine uptake. The decrease in these aromatic amino acids directly affects the synthesis and release of serotonin and catecholamines. The reader is referred to Fernstrom (2005) for a review of the biochemistry of BCAA transportation to the brain. Oral BCAAs have been examined as treatment for neurological diseases such as mania, motor malfunction, amyotrophic lateral sclerosis, and spinocerebral degeneration. Excitotoxicity as a result of excessive stimulation by neurotransmitters such as glutamate results in cellular damage after traumatic brain injury (TBI). However, because BCAAs also contribute to the synthesis of inhibitory neurotransmitters, it is unclear to what extent the role of BCAAs in synthesis



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8 Branched-Chain Amino Acids The branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) are nutrition- ally essential in that they cannot be synthesized endogenously by humans and must be sup- plied by diet. They differ from other essential amino acids in that the liver lacks the enzymes necessary for their catabolism. In addition to their function as structural components of proteins, BCAAs also seem to exert regulatory control of protein metabolism. In rodent tissue in vitro, increased con- centrations of BCAAs stimulate protein synthesis and inhibit protein catabolism, whereas other amino acid mixtures lacking BCAAs have no such influence. In humans, BCAAs inhibit protein catabolism, but have little effect on synthesis (see Matthews, 2005, for review). BRANCHED-CHAIN AMINO ACIDS AND THE BRAIN In the brain, BCAAs have two important influences on the production of neurotrans- mitters. As nitrogen donors, they contribute to the synthesis of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) (Yudkoff et al., 2005). They also compete for transport across the blood-brain barrier (BBB) with tryptophan (the precursor to serotonin), as well as tyrosine and phenylalanine (precursors for catecholamines) (Fernstrom, 2005). Ingestion of BCAAs therefore causes rapid elevation of the plasma concentrations and increases uptake of BCAAs to the brain, but diminishes tryptophan, tyrosine, and phenyl- alanine uptake. The decrease in these aromatic amino acids directly affects the synthesis and release of serotonin and catecholamines. The reader is referred to Fernstrom (2005) for a review of the biochemistry of BCAA transportation to the brain. Oral BCAAs have been examined as treatment for neurological diseases such as mania, motor malfunction, amyotrophic lateral sclerosis, and spinocerebral degeneration. Excitotoxicity as a result of excessive stimulation by neurotransmitters such as glutamate results in cellular damage after traumatic brain injury (TBI). However, because BCAAs also contribute to the synthesis of inhibitory neurotransmitters, it is unclear to what extent the role of BCAAs in synthesis 108

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109 BRANCHED-CHAIN AMINO ACIDS of both excitatory and inhibitory neurotransmitters might contribute to their potential ef- fects in outcomes of TBI. A list of human studies (years 1990 and beyond) evaluating the effectiveness of BCAAs in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase is presented in Table 8-1; this also includes supporting evidence from animal models of TBI. The occurrence or absence of adverse effects in humans is included if re- ported by the authors. USES AND SAFETY The Estimated Average Requirements (EARs) for leucine, isoleucine, and valine are 34, 15, and 19 mg/kg/day, respectively (IOM, 2005). Using the recommended intake for a 70 kg individual as a reference, the actual mean daily intake in the United States for each of the BCAAs is approximately threefold higher for men and approximately twofold higher for women (IOM, 2005). BCAA-enriched protein or amino acid mixtures or BCAAs alone have been used in a variety of metabolic disorders, such as chronic liver disease, encephalopathy, sepsis, and others, usually in an effort to reduce the uptake of aromatic amino acids by the brain and to raise low circulating levels. BCAA supplements are marketed to healthy individuals with claims that they enhance muscle mass, reduce soreness after exercise, and reduce central fatigue, although peer-reviewed research data rarely support these claims (Wagenmakers, 1999). A previous Institute of Medicine (IOM) committee considered the addition of higher amounts of specific amino acids, including BCAAs, to rations used during short-term, high-intensity combat operations. That committee found no evidence to recom- mend the addition of specific amino acids to those rations (IOM, 2006). As a result of claims for fitness benefits, athletes and military personnel striving to enhance physical performance may have BCAA intakes even higher than those of the general public. A survey by Lieberman et al. (2010) found that 23 percent of military personnel involved in combat arms and 47 percent of those in Special Forces were taking protein or amino acid supplements. A 2005 IOM report found no studies of adverse events associated with normal diets containing BCAAs or with infused supplemental doses up to 9.75 g, but there was no Toler- able Upper Intake Level (UL) determined because of the lack of dose-response data. Studies of acute or chronic oral administration of BCAAs have reported no adverse effects, even at a high single dose of 60 grams (Fernstrom, 2005). The outcomes of interest measured in these studies were related to physical performance, phenylketonuria, hepatic cirrhosis, and neurological and psychiatric diseases. It is, however, difficult to assess whether some of the outcomes that were not regarded as adverse effects would present a concern in a military setting. As an example, after examining one of the studies reporting no adverse effects, the committee concluded that excessive intake of BCAAs may be deleterious; in that study, oral doses of 10, 30, and 60 grams of BCAAs caused small increases in spatial recognition memory latency in healthy human subjects, but no changes in visual information processing or pattern recognition (Gijsman et al., 2002). The authors attributed the increased latency to a reduced ratio of (tyrosine+phenylalanine) to BCAAs, resulting in reduced transport of tyrosine and phenylalanine across the BBB, and hence reduced dopamine synthesis.

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110 NUTRITION AND TRAUMATIC BRAIN INJURY TABLE 8-1 Relevant Data Identified for BCAA Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Tier 1: Clinical trials Aquilani TBI Randomized, Postinjury, Disability Rating Scores (DRS) improved significantly for treated patients (p < et al., placebo- short-term parenteral 2008 controlled supplementation of 0.001; geometric mean of DRS decreased, trial BCAAs (500 mL of 4% from 23.17 to 19.68), while the score mixture of amino acids in placebo recipients remained virtually na=41 solution; provided 19.6 unchanged. 68% of treated patients rehabilitation g of BCAAs and 1.6 g achieved DRS scores that allowed them to patients arginine) for 15 days exit the vegetative or minimally conscious with a state. posttraumatic vegetative or From day 15 to discharge from minimally rehabilitation center, further significant conscious brain function improvement was detected in patients in treatment group (p < 0.03); state, 47±24 days no improvement was detected in placebo postinjury group. No adverse effects were mentioned. Aquilani Severe TBI Randomized, Postinjury, After 15 days, DRS for both treatment et al., placebo- 15 days of intravenous and placebo groups improved significantly (p < 0.02) compared to baseline. But 2005 controlled BCAA supplementation trial (19.6 g/day) improvement in treatment group was significantly greater than placebo group n=60 men (p < 0.004). with TBI After 15 days, significant increase in total BCAA was seen only in treated group (p < 0.01). Plasma tyrosine level increased in the treated group (p < 0.01), while tryptophan increased in the placebo group (p < 0.01). No adverse effects were mentioned.

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111 BRANCHED-CHAIN AMINO ACIDS TABLE 8-1 Continued Type of Type of Study Reference Injury/Insult and Subjects Treatment Findings/Results Evangeliou Refractory Pilot, Ketogenic diet, Adding BCAA to ketogenic diet resulted et al., epilepsy prospective supplemented by in a 100% seizure reduction in 3 patients 2009 trial powdered mixture of who had experienced seizure reduction on BCAA (45.5 g leucine, ketogenic diet alone. n=17 30 g isoleucine, and Four patients who already had > children, aged 24.5 g valine) 2 to 7 years 50% reduction on ketogenic diet Fat-to-protein ratio alone achieved an additional 20–30% with addition of BCAA reduction. changed from 4:1 to One patient, who had 20% reduction around 2:5:1 on ketogenic diet alone, achieved 50% reduction after adding BCAA. Addition of BCAA did not reduce seizure in patients who didn’t already experience seizure reduction on ketogenic diet only. No reduction in ketosis was found with the addition of BCAA. A slight increase in heart rate was reported at treatment initiation in 3 patients, but returned to normal without a reduction in the dose of BCAA. No other adverse effects were observed. Tier 2: Observational studies None found Tier 3: Animal studies Cole et al., TBI, lateral Adult male Postinjury, dietary After being treated with BCAA for 5 days 2010 fluid C57BL/ consumption of BCAAs after injury, BCAA level in injured mice (100 μM leucine, percussion J6 mice is not significantly different from sham brain injury isoleucine, and valine) mice. 5–7 weeks (LFPI) starting 2 days after old, 20–25 g In behavioral assessments, treated mice LFPI and continuing behaved no differently from control mice until 7 days after injury (p < 0.05). Hippocampal slices In vitro analysis showed that incubated with BCAA hippocampal slices from injured mice (100 μM) incubated with BCAA fully restored synaptic function (p < 0.05). a n: sample size.

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112 NUTRITION AND TRAUMATIC BRAIN INJURY EVIDENCE INDICATING EFFECT ON RESILIENCE Human Studies There have been no clinical trials to test the effects of BCAAs on resilience for TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy). Animal Studies There have been no animal studies addressing increased resilience for TBI. One study has examined the possibility of a negative influence of BCAAs at high concentrations. Contrusciere and colleagues (2010) noticed a high risk for amyotrophic lateral sclerosis among professional soccer players, and hypothesized that it could be due to excess consump- tion of sports beverages containing BCAAs. These beverages typically contain 1–3 grams of total BCAAs per 12-ounce serving. To test their hypothesis, the authors incubated rat neu- ronal cultures with 2.5–25 mM concentrations of BCAAs, and found that these extremely high doses induced toxicity. Note that normal BCAA concentrations in human cerebrospinal fluid are several orders of magnitude lower, ranging from ~5–15 μM (Garseth et al., 2001). A review of the literature was also conducted for outcomes related to the TBI disease process (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy). A search on the effects of BCAAs and epilepsy revealed several stud- ies that examined their impact in either the latency to a seizure or the duration of a sei- zure. Two studies used different animal models (pentylenetetrazol- or picrotoxin-induced seizures), but reported similar results: leucine and isoleucine increased the latency of the seizures (an indication of seizure threshold) compared to a controlled, balanced amino acid solution (Dufour et al., 1999; Skeie et al., 1994). The studies did differ, however, on the impact of valine in latency; while Skeie and colleagues (1994) found that valine at 300 mg/kg increased the mean latency time to onset of seizures, the study by Dufour found no such effect for valine. EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies Only one prospective randomized clinical study has investigated the efficacy of BCAAs as an acute treatment for TBI (Ott et al., 1988). Starting on the first day of hospitaliza- tion, 20 brain-injured patients were randomized to either a standard intravenous amino acid formula or one containing higher percentages of leucine (154 percent of the standard formula), isoleucine (153 percent), and valine (174 percent). The formulas had equivalent total calories and protein. Those patients on the BCAA-enriched formula exhibited positive nitrogen balance (+1.8%), whereas those on the standard formula were in negative balance (–8.0 percent) (Ott et al., 1988). Two small, randomized, placebo-controlled trials have been published reporting that BCAA supplementation enhanced cognitive recovery by patients with TBI (Aquilani et al., 2005, 2008). However, these studies began administering BCAAs anywhere from 19 to 140 days after injury, and therefore did not address the efficacy of BCAAs in treating the primary or secondary effects of neurotrauma. Seven additional studies have addressed BCAA supplementation in other forms of

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113 BRANCHED-CHAIN AMINO ACIDS trauma (reviewed in De Bandt and Cynober, 2006). Of these, four reported no beneficial effect on nitrogen balance, whereas three found positive results. The number of patients in each study tended to be small (ranging from 5 to 101, mean = 31) and the patients were heterogeneous in terms of type and severity of trauma. A prospective, randomized controlled study of patients undergoing curative hepatic resection found that perioperative oral nutrition including BCAAs resulted in higher serum erythropoietin concentrations than a control diet (for patients who did not have hepatitis). The authors suggested that higher erythropoietin concentrations might provide protection from ischemic injury (Ishikawa et al., 2010). When BCAAs were added as additional therapy to the ketogenic diet of children with refractory epilepsy, 13 out of 17 benefited, with a 50–100 percent seizure reduction com- pared to the ketogenic diet alone (Evangeliou et al., 2009). The authors suggested that BCAAs may not only increase the effectiveness of the ketogenic diet, but that the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein. Animal Studies Cole and colleagues reported that brain-injured mice exhibited cognitive improvement when treated with BCAA-supplemented drinking water (each BCAA at a concentration of 100 mM), beginning two days after injury (Cole et al., 2010). The injury was a 20 millisec- ond pressure pulse of saline to the dura, and hippocampal-dependent cognition was assessed using a conditioned fear response. Responses diminished by approximately 50% in the in- jured mice compared to sham controls, whereas injured mice drinking BCAA-supplemented water behaved no differently from controls. In addition to behavioral assessments, Cole et al. (2010) analyzed synaptic function in vitro. The excitatory postsynaptic potentials generated in hippocampal slices from injured mice were diminished compared to sham controls, but incubating the slices with BCAAs at concentrations of 100 μM fully restored synaptic func- tion (Cole et al., 2010). CONCLUSIONS AND RECOMMENDATIONS Leucine and other essential amino acids are necessary, and their benefit in increasing protein synthesis and lean body mass is well documented. However, there are not yet com- pelling data to support a recommendation to supplement rations with BCAAs to ameliorate or treat TBI. There is some indication from a pilot study that BCAAs might act synergisti- cally with a ketogenic diet in epilepsy, one of the many possible sequelae of TBI. The only randomized clinical trial (Ott et al., 1988) suggests that intravenous infusion of BCAAs may be beneficial for maintaining positive nitrogen balance following TBI, but the influence of BCAAs on morbidity and mortality was not reported. There is one encourag- ing animal study in which mice supplemented with BCAAs (dissolved in water at 100 mM) showed improvements in cognition and diminished excitatory potentials in hippocampal slices (Cole et al., 2010). Taken altogether, however, there is not enough evidence from animal studies to support initiating research in humans. Because a large percentage of military personnel take BCAAs as supplements to their diets, BCAAs should be included in the dietary intake assessments of TBI patients in medical treatment facilities to identify preinjury nutritional intake and status, as well as nutritional intake during the various stages of treatment. The data could be used to establish potential relationships between preinjury nutritional intake/status and recovery progress.

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114 NUTRITION AND TRAUMATIC BRAIN INJURY RECOMMENDATION 8-1. DoD should continue to monitor the literature on the effects of nutrients, dietary supplements, and diets on TBI, particularly those reviewed in this report but also others that may emerge as potentially effective in the future. For example, although the evidence was not sufficiently compelling to recommend that research be conducted on BCAAs, DoD should monitor the scientific literature for relevant research. REFERENCES Aquilani, R., P. Iadarola, A. Contardi, M. Boselli, M. Verri, O. Pastoris, F. Boschi, P. Arcidiaco, and S. Viglio. 2005. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Archives of Physical Medicine and Rehabilitation 86(9):1729–1735. Aquilani, R., M. Boselli, F. Boschi, S. Viglio, P. Iadarola, M. Dossena, O. Pastoris, and M. Verri. 2008. Branched- chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: A pilot study. Archives of Physical Medicine and Rehabilitation 89(9):1642–1647. Cole, J. T., C. M. Mitala, S. Kundu, A. Verma, J. A. Elkind, I. Nissim, and A. S. Cohen. 2010. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proceedings of the National Academy of Sciences of the United States of America 107(1):366–371. Contrusciere, V., S. Paradisi, A. Matteucci, and F. Malchiodi-Albedi. 2010. Branched-chain amino acids induce neurotoxicity in rat cortical cultures. Neurotoxicity Research 17:392–397. De Bandt, J.-P., and L. Cynober. 2006. Therapeutic use of branched-chain amino acids in burn, trauma and sepsis. Journal of Nutrition 136:308S–313S. Dufour, F., K. A. Nalecz, M. J. Nalecz, and A. Nehlig. 1999. Modulation of pentylenetetrazol-induced seizure activ- ity by branched-chain amino acids and [alpha]-ketoisocaproate. Brain Research 815(2):400–404. Evangeliou, A., M. Spilioti, V. Doulioglou, P. Kalaidopoulou, A. Ilias, A. Skarpalezou, I. Katsanika, S. Kalamitsou, K. Vasilaki, I. Chatziioanidis, K. Garganis, E. Pavlou, S. Varlamis, and N. Nikolaidis. 2009. Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: Pilot study and hypothesis. Journal of Child Neurology 24(10):1268–1272. Fernstrom, J. D. 2005. Branched-chain amino acids and brain function. Journal of Nutrition 135(6 Suppl.): 1539S–1546S. Garseth, M., L. R. White, and J. Aasly. 2001. Little change in cerebrospinal fluid amino acids in subtypes of mul- tiple sclerosis compared with acute polyradiculoneuropathy. Neurochemistry International 39(2):111–115. Gijsman, H. J., A. Scarna, C. J. Harmer, S. F. B. McTavish, J. Odontiadis, P. J. Cowen, and G. M. Goodwin. 2002. A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology 160(2):192–197. IOM (Institute of Medicine). 2005. Dietary Reference Intakes for energy, carbohydrate, fiber, fat, fatty acids, cho- lesterol, protein, and amino acids. Washington, DC: The National Academies Press. IOM. 2006. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. Ishikawa, Y., H. Yoshida, Y. Mamada, N. Taniai, S. Matsumoto, K. Bando, Y. Mizuguchi, D. Kakinuma, T. Kanda, and T. Tajiri. 2010. Prospective randomized controlled study of short-term perioperative oral nu- trition with branched chain amino acids in patients undergoing liver surgery. Hepato-Gastroenterology 57(99–100):583–590. Lieberman, H. R., T. B. Stavinoha, S. M. McGraw, A. White, L. S. Hadden, and B. P. Marriott. 2010. Use of dietary supplements among active-duty U.S. Army soldiers. American Journal of Clinical Nutrition 92(4):985–995. Matthews, D. E. 2005. Observations of branched-chain amino acid administration in humans. Journal of Nutrition 135(6 Suppl.):1580S–1584S. Ott, L. G., J. J. Schmidt, A. B. Young, D. L. Twyman, R. P. Rapp, P. A. Tibbs, R. J. Dempsey, and C. J. McClain. 1988. Comparison of administration of two standard intravenous amino acid formulas to severely brain- injured patients. Drug Intelligence and Clinical Pharmacy 22(10):763–768. Skeie, B., A. J. Petersen, T. Manner, J. Askanazi, and P. A. Steen. 1994. Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats. Pharmacology Biochemistry and Behavior 48(1):101–103. Wagenmakers, A. J. M. 1999. Amino acid supplements to improve athletic performance. Current Opinion in Clini- cal Nutrition and Metabolic Care 2:539–544. Yudkoff, M., Y. Daikhin, I. Nissim, O. Horyn, B. Lyhovyy, A. Lazarow, and N. I. 2005. Brain amino acid require- ments and toxicity: The example of leucine. Journal of Nutrition 135(6 Suppl.):1531S–1538S.