B Complex Articles for TBI and SCI

img_0066The Brain and B-Complex

B-Complex slide show:  b-complex-show

Nutritionally, we know that B complex vitamins are found in grains. Instructors tell us that B complex vitamins are critical to the development of the human brain, and they are utilized as cofactors in neurotransmitter production. They say that genetically, B complex vitamins may not be well absorbed, and that the B vitamin Dietary Reference Intakes (DRIs) may not be sufficient. Additionally, wheat gluten free patients may not be consuming adequate amounts. As nutritionists, we recognize the important of the B complex vitamins. Should a brain injury patient present, we would likely choose to normalize B complex levels. However, our treatment strategies should be evidence based. In reviewing the evidence, there are many animal studies that demonstrate efficacy of B complex vitamins after brain, spinal cord, and nerve injury, but what human studies are available?

This first human research study reviewed on spinal cord injury (SCI) was conducted with funding from the Canadian Institute of Health Research, by Walters et al. entitled “Evidence of dietary inadequacy in adults with chronic spinal cord injury” (2009). The findings were that B complex vitamins were deficient in women and men who suffered from chronic spinal cord injury. This study utilized 24 hour food frequency questionnaires in comparison with the DRIs. Subjects had experienced spinal cord trauma at least 12 months prior and used assistance for mobility. Dietary recalls were conducted in the home where recipes, food items, and brands could be verified by the double-pass method. Baseline FFQs were collected from 77 subjects initially and from 68 subjects at 6 months. Approximately, 50% of the participants regularly ingested supplements. Results showed that the men (n=63) had only 22% and women (n = 14) 14% of the DRI intake of thiamine. Men had a 5% of DRI intake of riboflavin and a 24% of DRI intake of pyridoxal phosphate. Folate intakes were 75% of DRI for men and 79% of DRI for women. Cobalamin intake was 6% of DRI for men and 29% of DRI for women. Prior to this study “little had been known about dietary intake or adequacy among people with SCI.” These researchers recognized that “the DRIs are intended for healthy-able bodied persons, and meeting the recommended intakes for nutrients does not necessarily provide enough for individuals with acute or chronic disease.”
A second human cross-sectional study on SCI evaluating cobalamin was conducted by Veterans Affairs to determine the prevalence of cobalamin deficiency in subjects with spinal cord injury (SCI). This study was by Petchkrua W (2003) entitled “Prevalence of vitamin B12 deficiency in spinal cord injury.” Medical records were reviewed retrospectively with prospective blood collection. Cobalamin deficiency is known to impair DNA synthesis and cause “white matter demyelination of spinal cord and cerebral cortex, and distal peripheral nerve” damage. “Common clinical findings are paresthesias and numbness, gait ataxia, depressed mood, and memory impairment.” These symptoms can be reversed with parenteral or high-dose oral cobalamin supplements, but can worsen and become irreversible if not treated early.” In this study 105 men ( mean age 54.1 years) with SCI mostly due to trauma were assessed. Fasting blood samples were utilized to evaluate nutrient levels including cobalamin, folate, and methylmalonic acid. Researchers concluded that “13% of patients with SCI …. had high MMA or low cobalamin levels. Neuropsychiatric symptoms possibly due to cobalamin deficiency were seen in half of these patients.” “Vitamin B12 deficiency was more common in persons with complete SCI or SCD.” “Given the possible risk or irreversible neuropsychiatric deficits, such as weakness or dementia, and given the relatively low cost of screening and the low cost and high efficacy of high-dose oral B12 replacement, clinicians should consider screening and early treatment of B12 deficiency.”

Four articles were identified relating to human cobalamin neuropathy research. The first article, a retrospective review, “Vitamin B for treating peripheral neuropathy” by Ang CD, et al. (2008) researched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE, EMBASE, and Philippine databases (of various timeframes) selecting random and quasi-random studies. “Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included”.  They only found that 1 trial showed a short term benefit in perceived vibration threshold with the supplementation of a thiamine derivative. Another study found that vitamin B supplementation was dose responsive in that higher doses seemed to reduce clinical symptoms such as pain.  Drugs worked better for pain.

The second human cobalamin neuropathy was a review article entitled “Is there an association of vitamin B12 status with neurological function in older people?” by Miles LM, et al (2015). This review evaluated the association of vitamin B12 status with neurological function and clinically relevant neurological outcomes. A systematic search of nine bibliographic databases (up to March 2013) identified twelve published articles describing two longitudinal and ten cross-sectional analyses.” Subjects were 65-81 years of age. “One longitudinal study reported no association, and four of seven cross-sectional studies reported limited evidence.” “One longitudinal study reported an association of vitamin B12 status with some …neurological outcomes.” “Three cross-sectional analyses reported no association. Overall, researches [found] there is limited evidence from observational studies to suggest an association of vitamin B12 status with neurological function in older people.”

In a third human cobalamin neuropathy study by Brito et al (2016) entitled “Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status.” The elderly Chileans consumed bread fortified with folate. 51 participants with serum vitamin B-12 concentrations < 120 pmol/L were given a single intramuscular injection of 10mg of vitamin B-12, 100mg vitamin B-6, and 100mg of vitamin B-1. “The response to treatment was assessed by measuring combined B-12 and neurophysiologic variables at baseline and 4 mo after treatment.” “Treatment produced consistent improvements in conduction in myelinated peripheral nerves.” “A total of 10 sensory potentials were newly observed in sural (leg calf muscle) nerves after treatment.”

In a fourth human cobalamin neuropathy article by Trippe et al (2016) “Nutritional management of patients with diabetic peripheral neuropathy with L-methyfolate-methylcobalamin-phyridoxal-5-phosphate: results of a real-world patient experience trial.” This researcher recently conducted a study investigating the effect of L-methylfolate-methylcobalamin-phyridoxal-5-phosphate supplementation on … peripheral neuropathy and found self-reported improvement. However, researchers did not look at clinical neurological function

As a collection, these human research studies and reviews demonstrate that SCI patients have vitamin B complex deficiencies as related to DRI. A second study reported only a small percentage of SCI patients have cobalamin deficiencies as related to DRIs, however, the majority of these SCI patients demonstrated clinical symptoms of cobalamin deficiency, indicating the DRIs could be insufficient for SCI. Finally, regarding neuropathies and cobalamin therapy, retrospective reviews show little correlation of cobalamin to relieving pain while prospective studies show that cobalamin improves neuronal conduction time, impulse strength, and surveyed patients report improvement.

There are not many vitamin B complex studies on TBI, SCI, or neuropathy utilizing human subjects partly due to the ethical issue of performing clinical trials on humans with TBI and as Haar mentions perhaps because there is not sufficient revenue in marketing B complex vitamins to recover a $2.5 billion pharmaceutical investment. Thus, many TBI and SCI studies are completed on animals.

In a piglet folate study by Naim et al. entitled “Folic acid enhances early function recovery in piglet model of pediatric head injury”,  3-5 day old piglets were utilized because they “provide a better model of the human brain than rodents.” “Piglets have a similar cortical grey-white differentiation gyral pattern and physiologic response to TBI in humans.” Half the piglets (n=15) “received inertial rotation of the head to induce TBI” while 15 were uninjured. Seven piglets were given folic acid (80ug/kg) 15 minutes post injury, while eight were given saline. Treatment continued for 6 days post injury. Of the 15 uninjured, 8 were folate controls and 7 were saline controls. “Piglets underwent cognitive and neurobehavioral tests 1 day and 4 days post injury. They were assessed on memory, learning, behavior and problem solving ability through a variety of tests.” “Cognitive Composite Dysfunction scores or CCDs were used to assess the neurobehavioral performance of the animals on days 1 and 4. The CCD scores for the piglets were based on a variety of tests including open-field behavior, a mirror test, glass barrier task, food cover task, balance beam performance, and maze test.” Results demonstrate “that there was significant improvement in functional ability of the injured piglets given folic acid between day 1 and day 4 post injury.” Additionally, results showed more rapid completion of the balance beam task, improved motor function, increased visual problem solving with folate supplementation. The “volume of brain injury was not found to be significantly reduced by folic acid supplementation.”
One study summarized riboflavin, niacin, pyridoxine and folate interventions on rodents entitled “Vitamins and nutrients as primary treatments in experimental brain injury: clinical implications for nutraceutical therapies (Haar et al, 2015)”. Haar found the benefits of riboflavin to “lead to substantial functional recovery in sensorimotor function and working spatial memory, less edema, less reactive astrocytes and smaller lesions (Barbre and Horne, 2006).” “Nicotinamide supplementation was shown to improve sensory, motor and cognitive function following frontal lobe injury (Hoane et al., 2003).” Further Hoane studies demonstrated “reduced apoptosis and improved blood-brain-barrier (BBB) function (Hoane et al., 2006)”, however Swan found “no improvement at a standard dose and increased impairment at higher doses (Swan et al., 2011).” Pyridoxine “showed tissue sparing effects at very high doses (600mg/kg) but not at lower doses (300mg/kg).” “Chronic high B6 supplementation has been shown to cause neural toxicity and gait and balance problems (Kringle et al., 1980).” Folic acid did not show benefits in this rodent model. Haar identified the “lack of clinical interest in many of these treatments” being “primarily a monetary issue. It is difficult to convince pharmaceutical companies to develop a drug that cannot be patented.” He states that both riboflavin and nicotinamide (neuroprotective effects) have beneficial research supporting their use in the treatment of TBI. The researcher additionally mentions that a combination therapy will be needed to treat TBI.

The Hoane rodent study on riboflavin of 2005 is entitled “Administration of Riboflavin Improves Behavioral Outcome and Reduces Edema Formation and Glial Fibrillary Acidic Protein Expression after TBI”. Reported are 41 male Sprague-Dawley that “were assigned to B2 or saline treatment conditions and received contusion injuries or sham procedures. Drug treatment was administered 15 minutes and 24 hours following the injury. The rats were examined on a variety of tests to measure sensorimotor performance and cognitive ability in the Morris water maze.” Results showed that riboflavin “significantly reduced behavioral impairments observed on the bilateral tactile removal test, and through improved acquisition of both reference and working memory tests”. B2 showed a reduction in the size of the lesion, reduced the number of GFAP+ astrocytes” (indicating healthier tissue) and significantly “reduced cortical edema.” The article states that “there is strong evidence in the literature that the mechanisms of action for riboflavin is its ability to reduce oxidative damage”. In Hoane’s earlier 2003 report, niacin was found to provide “a much stronger reduction in the initial magnitude of injury deficit on the bilateral tactile remove and working memory test than riboflavin.” Niacin’s “prevention of depletion of nicotinamide adenine dinucleotide (NAD+) and prevention of ATP depletion” are the likely mechanisms of action to improve TBI.

Hoane’s niacin study of 2003 was entitled “Treatment with Vitamin B3 improves functional recovery and reduced GFAP expression following TBI in rats”. In this cortical contusion model injury, 30 male Sprague-Dawley rats, 3 months old were utilized. Following injury, 9 rats were given niacin (500mg/kg) and 9 control rats were given saline solution (1ml/kg) 15 minutes and 24 hours post injury. Sham rats (n=12) received niacin or saline. “The Morris Water Maze (MWM) was used to assess cognitive function following injury.” Somatosensory dysfunction was tested through the Bilateral Tactile Adhesive Removal Test. Fine motor control was tested through a staircase model. Lesion analysis with the ImageToolSoftware was conducted 35 days post injury. GFAP immunochemistry was used to label reactive astrocytes. The “administration of niacin following cortical contusion injury ….significantly lessened the behavioral impairments observed following injury and led to a long-lasting improvement in functional recovery. More specifically, the data from the bilateral tactile removal test showed that administration of niacin following injury …prevented the occurrence of a working memory deficit in the MWM model. The acquisition of a reference memory task in the MWM was significantly improved compared to saline-treated rats following injury.” The “skilled forelimb use in the staircase task was not significantly improved” after treatment. “The administration of niacin following injury significantly reduced the number of GFAP+ reactive astrocytes. Glial Fibrillary Acidic Protein is an intermediate protein which is produced to regenerate astrocytes in the brain. While not well understood, smaller quantities of GFAP+ are thought to correlate with smaller quantities of scar tissue production, thus reduced lesion size.  In this 2003 article, Hoane and his team astutely proposed several potential mechanisms for the action of niacin including 1) ATP support, 2) poly-ADP ribose polymerase inhibition 3) lipid peroxidation inhibition and/or 4) apoptosis prevention. He confirmed the first mechanism in his 2005 article above. Overall, the benefits of niacin are significant in this rodent study, and Hoane’s researchers have shown consistently positive results through a number of rodent studies.

A complex study elucidating the folate mechanism is entitled “Folate regulation of axonal regeneration in the rodent central nervous system (CNS) through DNA methylation” written by Iskandar, BJ et al. (2010). This article discusses how the CNS, composed of the brain and spinal cord is difficult to repair after injury. This study is based upon research demonstrating axonal regrowth and functional recovery of the injured adult CNS with dose-dependent folate. This study was designed to identify the mechanism by which folate improves growth and recovery.

These researchers utilized a spinal cord injury model in rodents. Both cervical dorsal columns were injured and the left sciatic nerve completely transected. The Methods section is extensive depending upon the many experiments performed. The researchers identified the following information about the mechanism of folate in injury repair:

  • Injury induces expression of the folate receptor to attract folate to the injured site.
  • Global de-methylation of the spinal cord DNA accompanies injury.
  • The regeneration of injured CNS axons is inhibited due to dihydrofolate reductase.
  • Folate regulates its receptor activation and re-methylated DNA in a dose dependent manner.
  • Folate prevents DNA de-methylation in a dose dependent manner.
  • Reduced folate (via dihydrofolate reductase) is essential for folate’s pro-regenerative effects.
  • There is a direct, biphasic correlation between the proportion of regenerating afferent axons in the spinal cord, folate receptor expression, global DNA methylation, and methylation of a Gadd45a gene which is associated with spinal cord injury and neurite outgrowth.

The combined injury model is interesting because it causes an axonal response important to this research, however, it would not be a likely injury in rodents or humans. The results are important because they identify folate’s mechanism. Given our knowledge regarding the function of folate in methylation, this folate repair mechanism is likely to be similar in both rodents and humans. This report gives extensive support to folate’s role in CNS axonal repair, given the identification of the mechanisms.

Let’s summarize the various animal articles. In the piglet model, folate was found to improve cognitive and neurobehavior after TBI, however, folate was not found to reduce lesion size. In Haar’s rodent model, riboflavin was found to improve functional recovery in sensimotor function, working spatial memory, less edema, fewer reactive astrocytes and smaller lesions. Hoane found that riboflavin reduced behavioral impairment, lesion size, reactive astrocytes and cortical edema. Riboflavin likely works as a free radical scavenger. Niacin was found to increase sensorimotor function and cognitive function, decrease apoptosis, and increase blood-brain-barrier function. However, Swan saw no improvement at a standard niacin dose and toxicity at higher doses. Niacin’s likely mechanism is to provide NAD and ATP. Niacin has been shown to decrease both behavior impairments and reactive astrocytes, and prevent a working memory deficit. Niacin in this model did not improve skilled use. Pyridoxine showed tissue sparing at higher doses, but Kringle cautioned about neural toxicity. With folate, benefits were not shown in the rodent model in one report, however, benefits of folate in axonal regrowth and functional recovery have been demonstrated in other reports. The final report discussed identifies the mechanisms by which folate methylates DNA.

Presented with the brain injury patient, we have been trained to consider normalizing B complex vitamin levels. We know that B complex vitamins are critical for neural support, but we are encouraged to use evidence based therapies. Given the nature of TBI research and the difficulty of recovering a $2.5B pharmaceutical drug investment, more rodent studies are available than human as supportive evidence. The majority of human and animal researchers appear supportive of normalizing B vitamin levels with brain injury.

A final note, our government “gave away the internet” on October 1st to an international body. The United States developed the internet. Health care providers have enjoyed free access to the internet to research data for problem solving. Health care organizations have worked diligently to follow regulations enacted by the U.S. Government requiring these organizations to spend millions of dollars to protect patient information. Stiff penalties are levied for non-compliance. While the U.S. Government has provided poor internet security in years past, they no longer must provide any internet security to assist health care providers and organizations in protecting personal health data secure. We are all now at the world’s mercy. Let us all hope and pray that security and freedom prevail with our lost ownership and oversight.

References:

Ang CD, Alviar MJ, Dans AL, Bautista-Velez GG, Villaruz-Sulit MV, Tan JJ, Co HU, Bautista MR, Roxas AA. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008;(3):CD004573.

Brito A, Verdugo R, Hertrampf E, Miller JW, Green R, Fedosov SN, Shahab-Ferdows S, Sanchez H, Albala C, Castillo JL, Matamala JM, Uauy R, Allen LH. Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status. Am J Clin Nutr. 2016;103(1):250-7.

Haar, C.V., Peterson, T.C., Martens, K.M.,  Hoane, M.R. (2015). Vitamins and nutrients as primary treatments in experimental brain injury: clinical implications for nutraceutical therapies. Brain Research 1640, 114-129. doi: 10.1016/j.brainres.2015.12.03

Hoane, M.R., Akstulewicz, S.L., Toppen, J. Treatment with Vitamin B3 Improves Functional Recovery and Reduces GFAP Expression following Traumatic Brain Injury in Rats. (2003) Journal of Neurotrauma. 20(1): 1189-1199

Hoane, M. R., Wolyniak, J. G., & Akstulewicz, S. L. (2005). Administration of riboflavin improves behavioral outcome and reduces edema formation and glial fibrillary acidic protein expression after traumatic brain injury. Journal of Neurotrauma, 22(10), 1112-22. doi:http://dx.doi.org.libproxy1.usc.edu/10.1089/neu.2005.22.1112

Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, Hogan (2010). Folate
regulation of axonal regeneration in the rodent central nervous system through DNA
methylation. The Journal of Clinical Investigation, 120(5), 1603-1616.

Naim, M.Y., Friess, S., Smith, C., Ralston, J., Ryall, K., Helfaer, M.A. & Margulies, S.S. (2011). Folic acid enhances early functional recovery in a piglet model of pediatric head injury. Developmental Neuroscience, 32(5-6), 466-79. doi:http://dx.doi.org.libproxy2.usc.edu/10.1159/000322448

Miles LM, Mills K, Clarke R, Dangour AD. Is there an association of vitamin B12 status with neurological function in older people? A systematic review. Br J Nutr. 2015;114(4):503-8.

Petchkrua W, Burns SP, Stiens SA, James JJ, Little JW. Prevalence of vitamin B12 deficiency in spinal cord injury. Archives of Physical Medicine and Rehabilitation. November 2003, Vol.84(11): 1675-1679, doi:10.1053/S0003-9993(03)00318-6. http://www.sciencedirect.com.libproxy1.usc.edu/science/article/pii/S0003999303003186?via%3Dihub.

Trippe BS, Barrentine LW, Curole MV, Tipa E. Nutritional management of patients with diabetic peripheral neuropathy with L-methylfolate-methylcobalamin-pyridoxal-5-phosphate: results of a real-world patient experience trial. Curr Med Res Opin. 2016;32(2):219-27.

Walters JL, Buchholz AC, Martin Ginis KA. Evidence of dietary inadequacy in adults with chronic spinal cord injury. Spinal Cord (2009) 47, 318-322;doi:10.1038/sc.2008.134 published online 11 November 2008. http://www.nature.com/sc/journal/v47/n4/full/sc2008134a.html

Nutrition Director – Fish Presentation

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The following educational presentation has been developed for  School Child Nutrition Directors.   This education describes the benefits of consuming fish for brain health.

To begin presentation, please click link below:

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Bone Nutrients:

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Calcium

Medicine often points the finger to high sodium levels as being contributory to heart disease when in fact the culprit may be low calcium, potassium or magnesium levels. These nutrients work as a team to make nerve impulses conduct and muscles contract. These minerals must be present concurrently and in adequate amounts.

Potassium, magnesium and calcium levels can be measured in blood serum. However, the calcium blood measurement is not so useful, because when blood calcium is low, the body takes calcium out of bone to raise the blood calcium levels. When bone tissue is broken down in this manner, both calcium and phosphate are released from the bone into the blood stream, thus elevating blood serum levels. This regulation process is great to keep nerves conducting and muscles contracting. However, the process weakens bones because it removes calcium and phosphate. If this calcium and phosphate are never replaced, bone breakdown and eventually osteoporosis results.

Since blood calcium measurements do not give us an accurate indication of whether calcium levels are being maintained through dietary methods or from bone storage, medicine measures bone calcium levels through density scanning techniques such as DEXA scan. DEXA scan measurements that are between +1 and -1 are considered normal. Measurements between -1 and -2.5 are considered osteopenic (reduced bone mass) and measurements less than -2.5 are considered osteoporosis. More information can be found on http:// http://www.niams.nih.gov/health_info/bone/Bone_Health/bone_mass_measure.asp.

Noticeable physical indications of low blood calcium levels include muscle cramps, restless legs and broken bones. Muscles need adequate calcium, sodium, and potassium to contract and relax. Calcium supplements help relax a muscle cramp. This is due to lactic acid build up during exercise. Calcium may bind lactic acid, relaxing the muscle and releasing the cramp. Sparkling water and club soda, given their alkali nature, also help to neutralize the lactic acid relieving a muscle cramp. While massaging and stretching a tight muscle feels good, this may damage the fibers. Muscle relaxation and contraction is best restored when adequate minerals are provided. While a calcium supplement and alkali water, club soda, or sparkling water may be a temporary remedy to relieve muscle cramps or restless legs, a long term dietary and supplement plan will be important to maintain muscle, bone, and nerve health.

Calcium Sources

Because calcium is critical to humans, the bones have been cleverly designed to be the body’s mini storage units for calcium. We maintain these storage units and blood calcium levels through food intake and supplementation. Some of the best calcium foods according to WebMD are “cheese, yogurt, milk, sardines, dark leafy greens (spinach, kale, turnips, and collard greens) and orange juice”. You can find specific food calcium and nutrient information on NutritionData.com. Some of the best calcium supplements contain calcium citrate, calcium phosphate, and magnesium. Many supplements contain calcium carbonate which is lime. Current calcium recommendations range from 1000mg – 1500mg/day. Vitamin D also has an important role in transporting calcium into bone.

Collagen

While calcium supplementation is frequently recommended. It is less recognized that calcium citrate and phosphate are important supplements, given that they constitute a larger percentage of bone. The remaining portion of bone is composed of collagen. The collagen component of bone is never mentioned, yet it comprises anywhere from 10-30% of bone. Collagen is a flexible tissue found in young bone, tendons and ligaments. Collagen is found throughout the body in tissues, organs, joints, gums and teeth. In addition to calcium citrate and phosphate to make the calcium salts in bone, we need all of the nutrients to maintain the collagen network found in bone. The collagen network is formed by vitamin C and the amino acids lysine, proline and glycine. Collagen fibers can be damaged by injury, repetitive use, stretches or strains when muscles are weak. Collagen can additionally be damaged by our immune system. This is due to the attachment of wheat gluten to collagen fibers throughout the body. Our immune system sees wheat gluten and wheat defense proteins as foreign invaders. This causes the secretion of immune system chemicals contributing to arthritis, asthma, and many organ diseases. (More information can be found on http://www.wheatfreediseasefree.com.)

In summary, all of the nutrients: calcium citrate, phosphate, magnesium, vitamin D, vitamin C, lysine, proline and glycine must be present concurrently to build flexible collagen and healthy bone tissue. They can be found in a variety of foods and these supplements are available at nutrition stores. (Teeth may be a lysine storage site, and adequate lysine and vitamin C levels may contribute to gum and teeth health.)

So, we discussed calcium’s importance to muscle and nerves, and the body’s brilliant regulation mechanism for calcium such that when blood calcium levels are low, the body removes calcium from bone to maintain the blood calcium levels. As we mentioned, this regulation mechanism is great for maintaining nerve and muscle function, but not so great at maintaining bone strength and density. A good visual analogy might be a Corvette production line. All of the parts to build the Corvette must be supplied to build the car. If one part is missing, the technicians and robots build what may look like a car and feel like a car, but may not function like a car. One small part may make the difference. Bones and collagen work the same way. They are composed of many “parts” (calcium citrate, phosphate, magnesium, vitamin D, vitamin C, lysine, glycine, and proline). All nutrients must be supplied in adequate amounts for your body to build bone, tendon and ligaments. If “parts” are missing, the body may build structures that look like bone, tendon and ligaments, but they might not function that way. Bones may break easily and muscles may cramp easily. Restless legs may result. Tendons may tear. Adequate parts produce beautiful, zero to 60mph in 4 seconds Corvettes, and adequate nutrients produce healthy, functional bones, tendons and ligaments.

Why is Calcium Removed from Bone ??

As we discussed, our bodies remove calcium from bone tissue to maintain critical muscle and nerve function. This eloquent measure is likely designed to work temporarily when dietary/ supplemental calcium is insufficient. Alas, in osteoporosis, this calcium removal measure is apparently being forced to work long term. There is a second important reason calcium may be lost from bone. Many of our foods are acidic. The blood is carefully regulated to be around pH of 7.4, this is critical for chemical pathways. Acidic foods would drive the blood pH below 7.4.  Recycled bone calcium contains bicarbonate which acts as a pH buffer in the blood to balance these acidic foods, maintaining the pH. Alkali water, club soda, and sparkling water all bind acid to help maintain this normal blood pH. This process might be somewhat like bath water. If the bath water is too hot, cold water can be mixed with hot water to neutralize it’s effect. Finally, calcium can be removed from bone and excreted when the adrenals are fatigued. Both mental and physical stress, can fatigue the adrenals. Our high consumption modified grain and sugars fatigues our adrenals. As a result, calcium leaves the body.

Calcium Buildup in Tissues Other than Bone

Often, calcium builds up in tissues other than bone. Calcium buildup is found in breast tissue, kidney stones, gallstones, cysts and many other tissues, where it doesn’t belong. Why? What should we do? Should we reduce calcium intake to reduce this tissue buildup? Interestingly, calcium buildup in the wrong tissues appears to occur when individuals have insufficient dietary/supplemental calcium intake. Researchers have found that increasing dietary calcium and supplements decreases calcium buildup in the wrong tissues and increases calcium buildup in the right place, bone (Gul and Monga, 2014).

Your curious mind may ask, why is calcium showing up in the wrong tissues when dietary/ supplemental calcium levels are low? We would like to propose a theory to answer this question. We know that when blood calcium levels are low, recycled calcium (and phosphate) being released from bone to raise blood calcium levels. It is likely that the recycled bone calcium is structurally different from the calcium we eat in food and/or supplement, and possibly the recycled calcium from bone cannot be redeposited into bone tissue once blood levels normalize. Perhaps, the body can’t easily excrete excess recycled bone calcium, thus it builds up in tissues where it doesn’t belong. Certainly, releasing calcium from bone, to maintain blood calcium levels, was meant to be a temporary measure, not a long term process.

What is the impact of having recycled calcium delivered to the wrong tissues? “Insufficient intake of dietary calcium (<600mg/day) can increase… the risk of stone formation“, (Gambara, 2016). Gambara confirms that “stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance.” Research studies such as the 2012 NHANES find “a 70% increase from the 1994 NHANES” in urinary tract stone disease, (Gul and Monga, 2014). Thus, our calcium deficiencies are worsening. These researchers report that “newer research is finding that stones are associated with several serious morbidities”.

Researchers have found that calcium buildup in the form of hydroxyapatite in breast tissue contributes to breast cancer (Cooke, 2003). Let’s repeat this sentence. Calcium build up in breast tissue is involved with breast cancer. One in eight women will have breast cancer. Researchers also recognize that radiation can modify healthy cells and turn them into uncontrollable cancerous cells. Mammograms contain radiation and radiation damage is additive in the body. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue.  In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

How to Deliver Calcium to Bone

Given this information, how shall we best increase calcium in our bones and decrease calcium tissue deposits and stones?

One common solution, is to take a calcium supplement such as calcium citrate and/or calcium phosphate. Bone is composed of calcium citrate, calcium phosphate, magnesium, vitamin D, and collagen (vitamin C, lysine, proline, and glycine). It used to be that many calcium supplements were composed of calcium carbonate. Calcium carbonate is lime. Many supplements are now changing ingredients to calcium citrate or calcium phosphate. We need both.

Why calcium citrate? Citrate works in two ways. First, citrate is a buffer. Therefore, when the blood pH is low, citrate will buffer the pH and calcium will not be pulled from bone tissue to normalize pH. Alkali water, club soda or sparking water are alkali drinks that help to increase blood pH. Secondly, calcium citrate is found to combine well with phosphate and collagen components to make bone. Calcium citrate appears to be a key strength component in bone tissue. More information on citrate properties: https://www.sciencedaily.com/releases/ 2011/06/110608153548.htm. Finally, citrate and phosphate help remove calcium buildup in the wrong tissues: http://www.ncbi.nlm.nih.gov/pubmed/?term=breast%2C+hydroxyapetite %2C+citrate%2C+phosphate. Researchers found that citrus bioflavonoids and lemon peel inhibit stone formation: http://www.ncbi.nlm.nih.gov/pubmed/?term=27241030. This is critical information to the long term prevention calcium build up in the wrong tissues and maybe critical to the long term prevention of breast cancer. Many calcium supplements are now calcium citrate.

Calcium phosphate is the other important component of bone. Calcium citrate and phosphate can be found in supplements. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue. These deposits found on mammograms may contribute to the formation of breast cancer. In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

The Linus Pauling Institute has found that many other minerals and vitamins are found in bone such as magnesium, fluoride, sodium, vitamin A, D and K. More information can be found on: http://lpi.oregonstate.edu/mic/micronutrients-health/bone-health#minerals. More individuals than recognized may be deficient in vitamin A, as seen in dry eyes and in vitamin K as seen in nose bleeds. (Caution: vitamin K, found in leafy green vegetables, allows the blood to clot when vessels are damaged. Blood thinners interfere with vitamin Ks ability to clot blood. Ingesting additional vitamin K interferes with blood thinner drugs)

Secondly, drink plenty of fluids to produce at least 2.5L of urine per day (Gul and Monga, 2014). Gul recommends avoiding the colas which are acidic, yet not being quite as concerned with the “citric acid containing sodas, which include most clear soft drinks.” As we learned above, citric acid found in lemons and limes can be beneficial to bone health.

Remember that if you are eating a lot of protein, taking amino acids for brain or sports health, or drinking wine your blood may be more acidic which will pull carbonate from your bones to buffer the pH of your blood. So you may want to increase your calcium citrate or alkali water, club soda, and/or sparkling water consumption to balance these actions.

Finally, stressing your adrenals, the little walnut shaped organs that sit on top of your kidneys, (the adrenals produce neurotransmitters) results in the loss of calcium. Minimizing both mental stress activities and physical stress, often caused by the consumption of manufactured wheat and sugar, will help the adrenals. High glucose (grains, sugars) levels result in high stone levels (Gul and Monga, 2014).

References:

Cooke MM1, McCarthy GM, Sallis JD, Morgan MP. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1beta and cyclooxygenase-2 mRNA in human breast cancer cell lines. Breast Cancer Res Treat. 2003 May;79(2):253-63.

Gambaro G1, Trinchieri A2., Recent advances in managing and understanding nephrolithiasis/ nephrocalcinosis. F1000Res. 2016 Apr 18;5. pii: F1000 Faculty Rev-695. doi: 10.12688/ f1000research.7126.1. eCollection 2016

Gul Z1, Monga M2., Medical and dietary therapy for kidney stone prevention.
Korean J Urol. 2014 Dec;55(12):775-9. doi: 10.4111/kju.2014.55.12.775. Epub 2014 Nov 28.

Additional Materials:

Citrate helps reduce stone formation:

http://www.ncbi.nlm.nih.gov/pubmed/?term=22908773 http://www.ncbi.nlm.nih.gov/pubmed/?term=26614113

http://www.ncbi.nlm.nih.gov/pubmed/?term=20576821 http://www.ncbi.nlm.nih.gov/pubmed/?term=21747586

http://www.ncbi.nlm.nih.gov/pubmed/?term=17509313 http://www.ncbi.nlm.nih.gov/pubmed/?term=26582172 http://www.ncbi.nlm.nih.gov/pubmed/?term=27072174 http://www.ncbi.nlm.nih.gov/pubmed/?term=25855777 http://www.ncbi.nlm.nih.gov/pubmed/?term=26439475 http://www.ncbi.nlm.nih.gov/pubmed/?term

Chronic alcohol use may weaken bones: http://www.ncbi.nlm.nih.gov/pubmed/1854370.

EGCG (epigallocatechin gallate) found in green tea shows promise inhibiting the formation of kidney stones in rats:

http://www.ncbi.nlm.nih.gov/pubmed/?term=26281564 http://www.ncbi.nlm.nih.gov/pubmed/?term=16047215 http://www.ncbi.nlm.nih.gov/pubmed/?term=26898643

Mediterranean/fruit/vegetable diet may protect against stone formation: http://www.ncbi.nlm.nih.gov/pubmed/24502605

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.

Tryptophan’s Affect on Depression: A Review Article

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The Amino Acid Tryptophan produces the Neurotransmitter Serotonin.  Does Supplementing Tryptophan produce additional Serotonin to Attenuate Depression and Mood Disorders?

Southern California stood on high alert as depressed weapons expert, Christopher Dorner, declared war on fellow police officers. For days, he traveled through populated cities ambushing law enforcement officers. When Dorner was finally located in the remote San Bernardino forest, gunfire erupted. One officer died at the scene and a second was gravely injured. Both officers were medivaced to our Emergency Department at Loma Linda University. Hundreds of other police officers held a vigil in the parking lot. The injured officer was rushed past me into surgery. He would not survive. The following day, Christopher Dorner, an honorably discharged Navy reservist and former Los Angeles Police officer, took his own life.

Depression, according to World Health Organization estimates, will be the second highest cause of death (Muszyndska, et al., 2015). The affect of depression in the U.S. alone cost $210 billion in 2010 (Reus et al, 2015). Society experiences the increasingly common display of these depressive disorders on nightly television in the form of violent outbreaks, suicides, and school shootings.

Thus far, the major treatment for depression has been anti-depressant drugs. Although, treatment resistance occurs in over 20% of cases (Reus et al, 2015) and 50% of the patients experiencing Major Depressive Disorder will have episodic recurrences and chronic disease (Reus et al, 2015). During the first month of anti-depressant therapy, there is often no improvement in the depressive condition. Suicidal tendencies and inflicting self harm are a major side effect (Reus et al, 2015). Anti-depressant drugs are often designed to recycle the neurotransmitter chemicals present in an individual (Reus et al, 2015), typically not providing additional nutrients to raise neurotransmitter levels and rebuild damaged pathways. As a result, individuals are likely to be dependent upon anti-depressant drugs for an extended period. Eventually, the drug may no longer work or the individual may become treatment resistant ( Reus et al, 2015).
II. Tryptophan, Serotonin and the Alteration of Human Mood

The eventual cure for treating depression and mood disorders may be to provide nutrient based therapies with the goal of rebuilding major components of the neurological pathway systems involved with depression. One neurological pathway critical to affecting mood disorders generates the neurotransmitter serotonin (Bravo et al, 2013). Rebuilding the serotonin pathway to improve depressive-like symptoms may involve supplying the brain with the amino acid precursor, tryptophan.
Tryptophan hydroxylase Dopa Decarboxylase

Tryptophan ————–> 5-Hydroxytryptophan ————> Serotonin
(5-HTP) (5-HT, 5 -Hydroxytryptamine)

Cofactors: Vitamin B3, B9, Iron and Calcium Zinc, Vitamin B6 and C, Magnesium

(Educational Research, 2012)
This pathway illustrates the chemicals involved with the production of the neurotransmitter serotonin from the amino acid tryptophan. Tryptophan is a protein that cannot be made by humans, and thus is essential in the diet (Yao et al., 2011; Sarris & Byrne 2011). This pathway shows how tryptophan in the presence of the enzyme tryptophan hydroxylase (TH) and cofactors, vitamin B3, B9, iron and calcium, produces 5-hydroxytryptophan (5-HTP) (ERB, 2012). 5-HTP is able to cross the blood brain barrier (Patrick &Ames, 2015) where it is absorbed by brain nuclei which convert 5-HTP to serotonin (HT-hydroxytryptamine) in the presence of the enzyme dopa decarboxylase, and cofactors: zinc, vitamin B6, vitamin C, and magnesium (ERB, 2012). Cognitive behavior, sleep and mood are regulated by the neurotransmitter serotonin in humans, and pathway disturbances have been shown to exhibit anxiety, depression and cognitive disorders in humans (Cubero et al.,2011; Mendelsohn et al., 2009; Markus et al.,2005).

The serotonin production pathway is enhanced with many tryptophan or serotonin containing natural products in diets around the world. The natural plants, herbs and fungi that enhance the serotonin system include: Chinese saffron, Siberian Ginseng, African Griffonia, St. John’s Wort grown in Europe-Asia- Africa, African Kanna, Kava Kava from the Western Pacific, and mushrooms (Muszynska et al., 2015). The United States was prevented from using tryptophan and 5-HTP supplements late in the 1990s when a Japanese company supplied a tainted batch of product. The tainted batch caused eosinophilia-myalgia syndrome (EMS) in 1500 individuals including some deaths (Hill, et al., 1993; Druker, 2001). As a result, the FDA kept supplemental tryptophan unavailable until 2005. The scientific experiments described below will explore the use of supplemental tryptophan for the relief of depression and mood disorders in humans.

Tryptophan’s Effect on Human Mood

In this first experimental study, Mohajeri’s team hypothesized that positive emotional stimuli could be enhanced and negative stimuli reduced through dietary tryptophan. The article is titled “Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women”. Fifty-nine healthy women, 45-65 years old were randomly selected (age stratified) to compare a tryptophan fortified drink with placebo (Mohajeri, et al., 2015). Subjects experiencing psychiatric, neurological gastrointestinal disorders, receiving pharmaceuticals, diabetic, or pregnant, were excluded.

Subjects were baseline tested with four personality questionnaires: Dutch Personality Inventory, Depression Anxiety and Stress Scale, Aggression Questionnaire, and Barratt Impulsiveness Scale (Mohajeri, et al, 2015). Sleep/mood diaries were kept by the women. A large battery of pre and post tests assessed mental and physical sensations. Each woman was given tryptophan rich drinks for 19 days (Mohajeri, et al., 2015).

The experimental findings were similar between the placebo and tryptophan fortified drink in neuroticism, anxiety, impulsivity, depression and aggression. Cognitive results evaluated with the Rotary Pursuit Task, Rapid Visual Information Processing Task, Verbal Recognition Memory Test, and Driver Hazard Perception Test were similar (Mohajeri, et al, 2015). Final treatment increased high energy ratings on the Mental and Physical Sensations Scale. The Affective Go/No-Go Task slowed the negative word response time of the tryptophan drink group. The Facial Emotional Expression Rating Task showed no treatment effect, however, the intensity of anger lessened and overall happiness/mood improved (Mohajeri, et al, 2015)

These findings further showed that in the Simple Reaction Time Task, shorter reaction times resulted with the tryptophan drink. The Match to Sample Visual Search Task demonstrated an overall faster reaction time for the tryptophan supplemented group in locating targets (Mohajeri, et al., 2015). Evening mood and quality of sleep was evaluated through the self reported diary, Leeds Sleep Evaluation Questionnaire, and Thayer’s energetic arousal. ANCOVA found sleep and evening moods improved with the tryptophan drink (Mohajeri, et al, 2015). Subjects awoke fewer times during the night and rated their happiness higher. Mohajeri’s experiment found that the effect of the protein drink reduced anger, increased happiness/mood, improved sleep habits, and resulted in shorter reaction times. These four criteria relate directly to the depression related criteria analyzed in NHANES, as well as relate to criteria analyzed in the Beck Depression Inventory and Hamilton Psychiatric Rating Scale (Su et al, 2008; Raimo et al, 2015).

Tryptophan’s Effect on Human Mood and Sleep

This next experimental study is entitled “Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans” by R. Bravo and co-researchers. The hypothesis was whether sleep and depression/anxiety could be improved through a tryptophan rich cereal. This experiment is based upon the brain utilizing tryptophan to produce serotonin to regulate depression and anxiety (Cubero et al, 2011; Mendelsohn et al., 2009; Markus et al, 2005). Serotonin is then absorbed by the pineal gland to produce melatonin which is able to regulate sleep cycles and circadium rhythms (Bubenik & Konturek, 2011). Circadium rhythm disorders have been found to be related to depression and anxiety (Most et. al, 2010), and tryptophan supplementation has been found to increase circulating levels of both serotonin and melatonin (Aparicio et al, 2007)(Paredes et al., 2007)(Sanchez et. al., 2008a,b).

This tryptophan cereal experiment was performed with 35 caucasian volunteers (ages 55-75). These were healthy volunteers who experienced difficulty sleeping. They were not alcohol, drug users or smokers (Bravo et al., 2015). Individuals slept in their own homes and were asked to eat cereal for breakfast and dinner. During the first week of the experiment, Blevit Plus 8 control cereals containing (75mg tryptophan in 100g cereal) were eaten (Bravo et al, 2015). The second week, the Blevit Plus 8 experimental cereal (200mg tryptophan in 100g cereal) was eaten. The third week subjects returned to their normal diets (Bravo et al, 2015).

To analyze results, Sleep Analysis 5v.5.48 software and wrist actimetry were utilized to measure numerous sleep variables including actual sleep time, sleep efficiency, and number of awakenings (Bravo et al, 2015). Pre-test/post-test urinalysis through DRG kits were performed to measure 6-sulfatoxymelatonin (aMT6s) and 5-hydroxyindoleacetic acid (5-HIAA) which are melatonin and serotonin metabolites, respectively. The Cayman kit measured total antioxidant capacity of the urine to quantify the anti-oxidant activity of tryptophan (Bravo et al, 2015). Baseline Beck Depression Inventory and State-Trai Anxiety Inventory (STAI) tests were completed to evaluate pre-test/post-test depression and anxiety levels.

Bravo and colleagues found that when comparing sleep results during the tryptophan cereal treatment week with the control and normal diet weeks that sleep habits improved during the treatment week. Increased urine serotonin and melatonin metabolite findings following the high tryptophan cereal diet were statistically significant, as was urine anti-oxidant levels (Bravo et al, 2015). Trait anxiety did not differ from controls, however state anxiety reduced slightly. The Beck’s Depression Test results decreased, demonstrating fewer depression-like symptoms following the tryptophan cereal treatment diet (Bravo et al, 2015). Bravo and colleagues found that mood was positively correlated with the tryptophan diet.

III. A Systems Approach to Rebuilding the Serotonin Pathway

The experimental studies discussed in the last section found that supplementary tryptophan improved mood/depression-like disorders. The review studies discussed below reach beyond evaluating tryptophan as a single nutrient. These researchers have reviewed the mechanisms of the serotonin production pathway system and have considered the roles of additional nutrients that regulate and affect serotonin production. The first review paper evaluates the impact of omega-3 fatty acids which build brain tissue and suppresses inflammation. Additionally, this paper analyzes vitamin D’s role in regulation of the tryptophan hydroxylase enzyme which converts tryptophan to serotonin. The second review paper evaluates the biomarkers of gastrointestinal disease, including inflammation, as related to the biomarkers of depression.

Tryptophan, Vitamin D, and Murine Omega-3 Fatty Acids

In this review article written by Dr. Rhonda Patrick and Dr. Bruce Ames of the Nutrition and Metabolism Research Center in Oakland, California entitled “Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior” a physiological systems approach is applied. The authors discuss how serotonin pathway regulation and receptor access play important roles in pathway function. They write that when the serotonin pathway and the influential mechanisms are not working properly, a plethora of psychiatric disorders may arise including depression (Patrick & Ames, 2015) and social disturbances (Way et al, 2007; Varnas et al, 2004; Sanfey et al, 2007). Additionally, serotonin transporter polymorphisms have been identified which increase the risk of these psychiatric disorders in genetically predisposed individuals (Blair et al, 1995; Greenberg et al, 2000; Retz et al, 2004, Nielsen et al, 1994; Lesch et al, 1996). These researchers evaluate the mechanisms of vitamin D, eicosapentanoic acid (EPA), and docosahexanoic acid (DHA) in serotonin production.

Vitamin D regulates the conversion of tryptophan into serotonin by binding vitamin D response elements (VDRE) and transcriptionally acting upon the enzyme trytophan hydroxylase 1(TH1) (Patrick & Ames, 2015). TH1 is the enzyme responsible for converting tryptophan into serotonin in brain tissue (Patrick & Ames, 2015). Vitamin D has been found to be deficient in up to 70% of adults (Ginde, et al, 2009; Bailey et al, 2012; Mansbach et al, 2009). Deleterious cognitive effects of a vitamin D deficiency have been found in mice with genetic polymorphisms in their TPH genes (Zhang et al, 2004; Groves et al, 2013). These authors support vitamin D supplementation to help reduce psychiatric disease (Patrick & Ames, 2015).

EPA has a role in both the regulation of serotonin secretion and the suppression of inflammation (Gunther et al, 2010; Schlicker et al, 1987; Portanova et al, 1996). EPA inhibits generation of prostaglandins which decrease the release of serotonin and promote inflammation. EPA resolves depression caused by inflammatory cytokines (Su et al, 2014). In patients with gene polymorphisms the inflammatory process is pronounced (Su et al, 2010). While no mechanism has been found to explain how inflammation causes depression, it is known that serotonin is not released when inflammation is present. Stress and inflammatory cytokines are found to convert tryptophan into kynurenine instead of serotonin (Kiank et al, 2010) leading to increased anxiety (Patrick & Ames, 2015). EPA assists serotonin in performing its role to enhance positive social behavior and regulate mood (Patrick & Ames, 2015). In the average adult, dietary surveys show that a deficiency of EPA exists (U.S. Department of Agriculture, 2014).

DHA is important in the construction of the serotonin receptor (Patrick & Ames, 2015). The long chained, double bonded, DHA builds a fluid neuronal membrane allowing for proper positioning of the serotonin and dopamine receptors (Heron et al, 1980; Paila et al, 2010; Heinrichs et al, 2010). The serotonin receptors depend upon this accessibility given that receptor chains pass through the cell membrane seven times (Wassal et al, 2009; Escriba et al, 2007). Neuronal transmission of serotonin has found to decrease when omega-3 fatty acids are low (Chalon et al, 2006; de laPresa Owens & Innis, 1999). When additional omega-3 fatty acids are provided to humans, an increase of the serotonin metabolite 5-Hydroxyindoacetic acid (HIAA) has been found in the urine (Hibbeln et al, 1998). These authors recommend 1 gram per day of DHA and 2 grams of more of EPA (Patrick & Ames, 2015).

Patrick and Ames also highlighted the effectiveness of giving patients tryptophan or 5-HTP supplements to stimulate positive behaviors (Hudson et al, 2007; Young et al, 2007; aan het Rot et al, 2006). They stress the importance of exercise which causes branched chained amino acids (BCAA) to be utilized by muscle tissue, thereby increasing the tryptophan to BCAA ratio. Elevating this ratio increases tryptophan transport across the blood-brain barrier. Vitamin B6 and iron are important cofactors in serotonin production (Patrick & Ames 2015). In conclusion, these authors promote additional studies on the efficacy of utilizing tryptophan/5-HTP, murine omega-3 fatty acids (EPA and DHA), vitamin D, exercise, vitamin B6 and iron to restore normal cognitive function and acceptable social behavior in humans (Patrick & Ames, 2015). They see applications of this simple therapy in our prison system, where rehabilitation of individuals who impulsively display violent behavior could be most beneficial to society.

Tryptophan, Gastrointestinal Disease, and Inflammation

This second review article by Dr. Marta Martin-Subero and colleagues from Spain and Australia is entitled “Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways”. This article is most current in addressing the systemic effects of gut inflammation given the recent attention given to leaky gut syndrome. Much of leaky gut syndrome can be attributed to the high consumption of wheat germ agglutinun lectins and gluten proteins (Falth-Magnusson et al., 1995) in the diet. Martin-Subero and colleagues sought to connect the inflammatory pathologies of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn’s Disease (CD) and depression.

In comparing depression with IBD, both have alternating remissions and inflammatory episodes that appear to concurrently exist (Martin-Subero et al, 2015). Patients with IBD have a 2-3x greater likelihood of having depression (Martin-Subero et al, 2015). One case-controlled study of 12,500 individuals, found that depression and anxiety preceded a UC diagnosis (Kurina, MMS (15)). Chronically, a damaged leaky gut may deliver intestinal lipopolysaccharide from gut bacterial capsules and wheat lectins/gliadins into the blood serum resulting in a systemic inflammatory response (Falth-Magnusson et al., 1995). This inflammation may attenuate the release of serotonin promoting depression and psychosomatic disorders (Martin-Subero et al, 2015).

Researchers found that there are several pathways utilized by both IBD and depression. Initially, the levels of interleukins, tumor necrosis factor alpha, and interferon are increased in both conditions while levels of immune suppressive cytokines are decreased (Martin-Subero et al, 2015). Acute phase proteins and C-reactive protein are both increased in depression and IBD. Second, increased levels of protein, DNA, and lipid damage are seen, as well as decreased levels of some anti-oxidants. Oxidative and nitrosative stress plus reactive oxygen and nitrogen species are increased, (Martin-Subero et al, 2015) possibly due to mitochondrial dysfunction. Lower zinc levels are found in both conditions. Third, similar levels of serum antiphospholipid antibodies have been found in CD, UC, and depressed individuals. Autoimmune disorders are common with IL-6 and Th-17 levels increased (Martin-Subero et al, 2015).

In a fourth coordination of concurrent biomarkers in depression and gastrointestinal disease, both conditions activate indoleamine 2,3-dixoygenase (IDO) which converts tryptophan to kynurenine, transcending down the TRYCAT (tryptophan catabolism) pathway such that serotonin cannot be produced (Reus et al, 2015). Increased TRYCAT levels in conjunction with lower plasma tryptophan levels contribute to neurotoxic processes and depression-like symptoms (Martin-Subero et al, 2015; Maes et al, 2011). These results, including the presence of a leaky gut, cytokine elevations, TRYCAT induction and oxidative/nitrosative stress (Martin-Subero et al, 2015) in both conditions lead these researchers to propose an association between depression and IBD (Martin-Subero et al, 2015). To provide further evidence that some association exists, they note that TNF-alpha antagonist and anti-depressant drugs improve both IBD and depression( Banovic et al, 2009; Raison et al, 2013; Goodhand et al, 2012; Martin-Subero et al, 2015).

IV. Conclusion

As depression becomes the second highest cause of death, society will continue to suffer from the acts of the psychologically disturbed. The neurotransmitter serotonin has been found to improve mood and depressive disorders. Anti-depressant drugs costing millions of dollars have helped with short term treatment, but are not replacing the nutrient deficiencies in these affected individuals. An inexpensive and long term solution might be to utilize the basic biochemistry and physiological sciences taught in our medical professions to design therapies that provide adequate levels of all nutrients involved in neurotransmitter pathway systems. Fortifying food with tryptophan in conjunction with necessary cofactors produces serotonin and improves psycho-social behaviors. Fortifying individuals with vitamin D activates the conversion of tryptophan to serotonin. Fortifying individuals with the murine fish oils, EPA and DHA, decreases inflammation and improves the accessibility of serotonin binding receptors on neurons. Treating the complete serotonin pathway system may well provide an inexpensive, scientifically based, long-term solution. These treatments may benefit society through the attenuation of the potentially aggressive behaviors caused by depression and mood disorders.

References:
aan het Rot, M., Moskowitz, D. S., Pinard, G., and Young, S. N. (2006) Social behaviour and mood in everyday life: the effects of tryptophan in quarrelsome individuals. J. Psychiatry Neurosci. 31, 253–262

Aparicio S, Garau C, Nicolau MC, Rivero M, Rial RV (2007) Chrononutrition: use of dissociated day/night formulas to improve the development of the wake-sleep rhythms. Effects of tryptophan. Nutr Neurosci 10(3–4):137–143

Bailey, R. L., Fulgoni, V. L., 3rd, Keast, D. R., Dwyer, J. T. (2012) Examination of vitamin intakes among US adults by dietary supplement use. J. Acad. Nutr. Dietetics 112, 657–663

Banovic I, Gilibert D, Cosnes J. Perception of improved state of health and subjective quality of life in Crohn’s disease patients treated with infliximab. J Crohns Colitis. 2009; 3(1): 25-31

Blair, R. J. (1995) A cognitive developmental approach to mortality: investigating the psychopath. Cognition 57, 1–29

Bravo R1, Matito S, Cubero J, Paredes SD, Franco L, Rivero M, Rodríguez AB, Barriga C (2012). Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Age (Dordr). 2013 Aug;35(4):1277-85. doi: 10.1007/s11357-012-9419-5. Epub 2012 May 24.

Bubenik GA, Konturek SJ (2011) Melatonin and aging: pros- pects for human treatment. J Physiol Pharmacol 62(1):13–19

Chalon, S. (2006) Omega-3 fatty acids and monoamine neuro- transmission. Prostaglandins Leukot. Essent. Fatty Acids 75, 259–269

Crockett, M. J. (2009) The neurochemistry of fairness: clarifying the link between serotonin and prosocial behavior. Ann. N. Y. Acad. Sci. 1167, 76–86

Cubero J, Otalora BB, Bravo R, Sánchez CL, Franco L, Uguz AC, Rodríguez AB, Barriga C (2011) Distribution of 5-HT receptors in the mammalian brain. Trends Cell Mol Biol 6:41–46

de la Presa Owens, S., and Innis, S. M. (1999) Docosahexaenoic
and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets. J. Nutr. 129, 2088–2093

Druker SM, “How The U.S. Food And Drug Administration Approved Genetically Engineered Foods Despite The Deaths One Had Caused And The Warnings Of Its Own Scientists About Their Unique Risks”, Alliance For Bio-Integrity, 2001

Educational Research (ERB); http://wheatfreediseasefree.com/category/neurotransmitter-brain-food/

Escriba, PV, Wedegaertner, PB, Goni FM and Vogler O. (2007) Lipid-protein interactions in GPCR-associated signaling. Biochim. Biophys. Acta 1768, 836-852.

Fälth-Magnusson K, Magnusson KE. Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease. Pediatr Allergy Immunol. 1995 May;6(2):98-102

Forbes Magazine, 2013 http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/

Ginde, A. A., Liu, M. C., and Camargo, C. A., Jr. (2009) Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch. Intern. Med. 169, 626–632

Goodhand JR, Greig FI, Koodun Y, et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm Bowel Dis. 2012; 18(7):1232-1239

Greenberg, B. D., Li, Q., Lucas, F. R., Hu, S., Sirota, L. A., Benjamin, J., Lesch, K. P., Hamer, D., and Murphy, D. L. (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am. J. Med. Genet. 96, 202–216

Groves, N. J., Kesby, J. P., Eyles, D. W., McGrath, J. J., Mackay-Sim, A., and Burne, T. H. (2013) Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav. Brain Res. 241, 120–131

Gu ̈nther, J., Schulte, K., Wenzel, D., Malinowska, B., and Schlicker, E. (2010) Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266. Naunyn Schmiedebergs Arch. Pharmacol. 381, 21–31

Heinrichs, S. C. (2010) Dietary omega-3 fatty acid supplemen- tation for optimizing neuronal structure and function. Mol. Nutr. Food Res. 54, 447–456

Heron, D. S., Shinitzky, M., Hershkowitz, M., and Samuel, D. (1980) Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes. Proc. Natl. Acad. Sci. USA 77, 7463–7467

Hibbeln, J. R., Linnoila, M., Umhau, J. C., Rawlings, R., George, D. T., and Salem, N., Jr. (1998) Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol. Psychiatry 44, 235–242

Hill RH Jr, Caudill SP, Philen RM, Bailey SL, Flanders WD, Driskell WJ, Kamb ML, Needham LL, Sampson EJ, “Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome.”, Arch Environ Contam Toxicol. 1993 Jul;25(1):134-42.

Hudson, C., Hudson, S., and MacKenzie, J. (2007) Protein- source tryptophan as an efficacious treatment for social anxiety disorder: a pilot study. Can. J. Physiol. Pharmacol. 85, 928–932

Kiank, C., Zeden, J. P., Drude, S., Domanska, G., Fusch, G., Otten, W., and Schuett, C. (2010) Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on im- munosuppression in mice and humans. PLoS ONE 5, e11825

Kurina LM, Goldacre MJ, Yeates D, Gill LE, Depression and anxiety in people with inflammatory bowel disease. J Epidemiol Community Health. 2001; 55(10):716-720

Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri,S.,Benjamin,J.,Mu ̈ller,C.R.,Hamer,D.H.,andMurphy, D. L. (1996) Association of anxiety-related traits with a poly- morphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531

Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new “5-HT” hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of deterimental tryptophan catabolites (TRYCATS), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3): 702-721

Mansbach, J. M., Ginde, A. A., and Camargo, C. A., Jr. (2009) Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 124, 1404–1410

Markus CR, Jonkman LM, Lammers JHCM, Deut NEP, Messer MH, Nienke R (2005). Evening intake of α-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention. Am J Clin Nutr 81:1026–1033

Martin-Subero M1, Anderson G2, Kanchanatawan B3, Berk M4, Maes M3 (2015).
Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways. CNS Spectr. 2015 Aug 26:1-15. [Epub ahead of print]

Mendelsohn D, Riedel WJ, Sambeth A (2009). Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 33:926-952.

Mohajeri MH, Wittwer J, Vargas K, Hogan E, Holmes A, Rogers PJ, Goralczyk R, Gibson EL (2015). Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women. Br J Nutr. 2015 Jan 9:1-16. PMID: 25572038

Most EIS, Scheltens P, Van Someren EJW (2010) Prevention of depression and sleep disturbances in elderly with memory- problems by activation of the biological clock with light— a randomized clinical trial. Trials 11:19

Muszyńska B1, Łojewski M1, Rojowski J2, Opoka W2, Sułkowska-Ziaja K1. Natural products of relevance in the prevention and supportive treatment of depression (2015). Psychiatr Pol. 2015;49(3):435-453. doi: 10.12740/PP/29367. PMID: 26276913

Nielsen, D. A., Goldman, D., Virkkunen, M., Tokola, R., Rawlings, R., and Linnoila, M. (1994) Suicidality and 5- hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch. Gen. Psychiatry 51, 34–38

Paila, Y. D., Ganguly, S., and Chattopadhyay, A. (2010) Metabolic depletion of sphingolipids impairs ligand binding and signaling of human serotonin1A receptors. Biochemistry 49, 2389–2397

Paredes SD, Terrón MP, Valero V, Cubero J, Barriga C, Reiter RJ, Rodríguez AB (2007) Tryptophan increases nocturnal rest and affects melatonin and serotonin serum levels in oldringdove. Physiol Behav 90:576–582, Pergamon-Elsevier Science Ltd. (I.S.S.N.: 0031–9384)

Patrick, R. P., and Ames, B. N. (2014) Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 28, 2398–2413

Portanova, J. P., Zhang, Y., Anderson, G. D., Hauser, S. D., Masferrer, J. L., Seibert, K., Gregory, S. A., and Isakson, P. C. (1996) Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J. Exp. Med. 184, 883–891

Raimo S1, Trojano L, Spitaleri D, Petretta V, Grossi D, Santangelo G. (2015) Psychometric properties of the Hamilton Depression Rating Scale in multiple sclerosis. Qual Life Res. 2015 Aug;24(8):1973-80. doi: 10.1007/s11136-015-0940-8. Epub 2015 Feb 11.

Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013; 70(1): 31-41

Retz, W., Retz-Junginger, P., Supprian, T., Thome, J., and Ro ̈sler, M. (2004) Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. Behav. Sci. Law 22, 415–425

Reus GZ, Jansen K, Titus S, Carvalho AF, Gabbay V, Wuevedo J. (2015) Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. Journal of Psychiatric Research. 2015; 68(2015) 316-328

D, Riedel WJ, Sambeth A (2009) Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 33:926–952

Sánchez S, Sánchez CL, Paredes SD, Barriga C, Rodríguez AB (2008a) Circadian levels of serotonin in plasma and brain after oral administration of tryptophan in rats. Basic Clin Pharmacol 104:52–59

Sánchez S, Sánchez CL, Paredes SD, Rodríguez AB, Barriga C (2008b) The effect of tryptophan administration on the circadian rhytms of melatonin in plasma and the pineal gland of rats. J Appl Biomed 6:177–186

Sanfey, A. G. (2007) Social decision-making: insights from game theory and neuroscience. Science 318, 598–602

Sarris J, Byrne GJ (2011). A systemic review of insomnia and complementary medicine. Sleep Med Rev 15:99-106

Schlicker, E., Fink, K., and Go ̈thert, M. (1987) Influence of eicosanoids on serotonin release in the rat brain: inhibition by prostaglandins E1 and E2. Naunyn Schmiedebergs Arch. Pharmacol. 335, 646–651

Su, K. P., Lai, H. C., Yang, H. T., Su, W. P., Peng, C. Y., Chang, J. P., Chang, H. C., and Pariante, C. M. (2014) Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol. Psychiatry 76, 559–566

Su, K. P., Huang, S. Y., Peng, C. Y., Lai, H. C., Huang, C. L., Chen, Y. C., Aitchison, K. J., and Pariante, C. M. (2010) Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol. Psychiatry 67, 550–557

Sung, HM, Kim JB, Park YN, Bai DS, Lee SH, Ahn HN. A study on the reliability and the validity of Korean version of the Beck Depression Inventory-II (BDI-II) J Korean Soc Biol Ther Psychiatry. 2008;14:201–12.

US Department of Agriculture, ARS. (2014) Nutrient Intakes from Food: Mean Amounts Consumed per Individual, by Gender and Age, US Department of Agriculture, Washington, DC

Varna ̈s, K., Halldin, C., and Hall, H. (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum. Brain Mapp. 22, 246–260

Wassal SR and Stillwell W (2009). Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes. Biochim. Biophys. Acta 1788, 24-32.

Way, B. M., Lac ́an, G., Fairbanks, L. A., and Melega, W. P. (2007) Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey. Neuroscience 148, 937–948

Yao K, Fang J, Yin YL, Feng ZM, Tang ZR, Wu G (2011) Tryptophan metabolism in animals: important roles in nu- trition and health. Front Biosci (Schol Ed) 1(3):386–397

Young, S. N., Rot, M., Pinard, G., and Moskowitz, D. S. (2007) The effect of tryptophan on quarrelsomeness, agreeableness, and mood in everyday life. Int. Congr. Ser. 1304, 133–143

Young, S. N., and Leyton, M. (2002) The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol. Biochem. Behav. 71, 857–865

Zhang, X., Beaulieu, J. M., Sotnikova, T. D., Gainetdinov, R. R., and Caron, M. G. (2004) Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305, 217

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Amino Acid Therapy for TBI and Concussion: A literature review

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Amino Acid Therapy for Traumatic Brain Injury: A Literature Review

Introduction: High school biology has long instructed on the importance of protein in construction of neurons, cell membrane, and neurotransmitters. College biochemistry students memorize the twenty amino acids, and their required presence for protein transcription. Yet, in healing traumatic brain injury (TBI), elemental amino acid therapy is rarely considered. TBI is our leading cause of death among the population under age 44 given combat casualties, sports-related injuries, and motor vehicle accidents. TBI brings lingering deficits in concentration, depression, sleep-wake cycle, behavior, and motor skills. In addition, are the long term sequelae of chronic traumatic encephalopathy, dementia, and Alzheimer’s disease. While enteral/parenteral nutrition formulas supply the eight essential amino acids, they fail to consider the TBI hyper- metabolic state requiring the increased efficiency of elemental amino acids for healing. The Institute of Medicine Report (IOM, 2011) found that when elemental nutrient substrate was provided, second injury did not occur. The hypothesis is that nutritional interventions of elemental amino acids will effect a more complete recovery from TBI, than essential amino acids alone.

Methods: Study design was to search PUBMED with the keywords “TBI” and “Amino Acid Therapy”. The goal was to review 10 articles. With limited human studies, rodent studies were included. Criteria reported: Study Title, Journal/Date, Brief Summary, Purpose, Population, Setting, Research Design, Framework, Methods, Intervention, Significant Results, Conclusions, Significant Findings, Limitations, and Implications.

Results: Of the 10 primary studies, cysteine alleviated behavioral/cognitive deficits, regulated cytokines, and reduced oxidative stress (including lipid peroxidation). Aspartate was found to improve motor deficits. Arginine reduced contusion size, maintained cerebral perfusion pressure, and reduced intracranial pressure. While higher glutamine levels have been associated with worse outcome, which one study confirmed, supplying glutamine and alanine did not elevate brain glutamine levels nor predict a worse outcome. In two studies, the University of Pennsylvania astutely combined amino acids using branched-chained amino acid (BCAA) therapy. Hippocampal behavioral deficits, cognitive impairment, abnormal EEG, and wakefulness were restored. Additionally, in 2 review articles: the IOM found efficacy with protein, omega-3, choline, B-complex vitamins, and other nutrients (IOM 2011) and the Army found efficacy with omega-3, vitamin, D, zinc, and glutamine (Scrimgeor, 2014).

Conclusion: Beneficial reports of individual amino acid therapy ameliorating behavioral and motor deficits continue to emerge in both human and rodent studies.  In addition to the important findings described above, there are four clinically relevant concepts that will be applicable to research going forward.  First, if damaged neurons are stimulated to complete an energy dependent process, they die.  This finding may underscore the concept of mental rest for brain trauma patients.  Second, while amino acids may resolve TBI induced deficit, discontinuing supplementation restores the deficit.  Third, supplying amino acids thought to have little blood-brain-barrier penetration are found to significantly improve TBI.  Finally, TBI patients were found to benefit from increased amounts of both essential and so-called non-essential amino acids.  This, in part, confirms the hypothesis that elemental amino acids improve TBI. Only the University of Pennsylvania has creatively combined elemental amino acids for TBI therapy. The results were substantially impressive, such that they applied for a patent!

 

 

Study Title (1)

N-Acetylcystene and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats

Journal and Date

Neurochemical Research, April 2014

Brief Summary

“Oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI).” “Using Sprague-Dawley rats, researchers demonstrated that N- acetylcysteine (NAC) and selenium (Se) showed protective affects on the TBI- induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.”

Purpose

To make a research contribution to therapies for untreated traumatic brain injury.

Sample Population

Thirty-Six, 4 month-old male Sprague-Dawley rats

Setting

Neuroscience Research Center Lab, Suleyman Demirel University, Isparta Turkey

Research Design

Randomly selected, controlled/treatment groups, prospective, experimental rats

Theory/Framework

Amino acids supplied to the traumatized brain alleviate oxidative stress.

Methods

Marmarou’s weight drop model was used to induce TBI in rats. “Rats were divided into four groups:” 1) control group – placebo, 2) TBI group, 3) TBI group treated with gastric lavage NAC (150mg/kg) at 1, 24, 48, 72h after TBI, 4) TBI group treated with Se (NaSe 1.5mg/kg) intraperitoneal at 1, 24, 48, 72h after TBI. Brain cortex homogenate and plasma erythrocytes used to measure lipid peroxidation (LP), GSH, protein, vitamin A, vitamin E, B-carotene, vitamin C, TAS/ TOS, and cytokine levels. SPSS and Mann-Whitney U test used for analysis.

Intervention

TBI with 150mg/kg NAC given to group 3 and 1.5mg/kg Se given to group 4.

Significant Results

“LP is a biomarker of oxidative stress.” “Results showed that LP in brain cortex (p<0.05), plasma (p < 0.05) and erythrocyte (p < 0.01) and TOS levels (p<0.001) in the brain cortex in TBI group were significantly higher than the control. Hence oxidative stress..was increased by TBI.” “Brain cortex vitamin A, B-carotene, vitamin C, vitamin E, TAS, GSH and plasma vitamin E, IL-4, and brain cortex/ plasma levels of GSH-Px decreased by TBI.”

Conclusions

“Administration of NAC and Se caused decrease in LP of the brain cortex (p<0.05), plasma (p<0.05), and erythrocytes (p<0.01) in the TBI + NAC and TBI + Se group were significantly lower than the TBI group, respectively.” “IL-1B levels decreased and GSH, vitamin E, and IL-4 values increased.”

Significant Findings

“Se modulated the balance of oxidant and antioxidant, pro- and anti-inflammatory cytokines in rates by down-regulating the levels of pro-inflammatory (IL-B) cytokine and upregulating the levels of anti-inflammatory (IL-4) cytokines.”

Limitations

Transferring mouse model TBI therapies to human TBI therapies

Implications for Practice

N-acetyl-cysteine and selenium may be viable therapies to help alleviate human suffering from TBI.

Study Title (2)

Efficacy, dosage and duration of action of branched chain amino acid therapy for traumatic brain injury

Journal and Date

Frontiers in Neurology, March 30, 2015

Brief Summary

“Traumatic Brain Injury (TBI) results in long-lasting cognitive impairments for which there is currently no accepted treatment.” “Previous studies identified a novel therapy consisting of branched chain amino acids (BCAA), which restored normal mouse hippocampal responses and ameliorated cognitive impairment following fluid percussion injury. However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown.” Results from this study show that “alterations in hippocampal function” “are reversible with at least 5 days of BCAA treatment and that sustaining this effect can occur with continuous treatment.”

Purpose

To contribute BCAA dosage amounts to existing BCAA TBI therapies data.

Sample Population

C57Bl/J6 Jackson Laboratory mice, 5 to 7 weeks old, 20-25g, male.

Setting

Research laboratories in Oregon and Philadelphia with an ambient temperature of 23C and humidity of 25C, 12h light/12h dark cycle, 100lux. Free access to food/ water. Performed within NIH Lab Animal Guidelines.

Research Design

Randomly selected, controlled, fluid percussion injury prospective, experimental

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

C57BL/J6 mice sustained fluid percussion injury (FPI) with a 48 hour recovery. Mice were individually housed then treated with BCAA supplemented or unsupplemented water. Concurrent experiments were conducted to determine duration of BCAA action and effective BCAA concentration. Control consisted of untreated tap water. Following TBI recovery, animals were fear conditioned. Then, 24 hours later were observed for freezing in the conditioning box. A lower freezing percentage is indicative of impaired contextual memory.

Intervention

Anesthesia, craniectomy, FPI of 1.8-2.1 atm, sutures, either 50mM BCAA or 100mM BCAA or regular tap water for 2, 3, 4, 5, 10 days.

Significant Results

“Injured mice that received BCAA treatment showed a significantly greater freezing response on average compared to the untreated FPI mice when treatment was delivered for 5 or 10 consecutive days.”

Conclusions

“Data establish that BCAA therapy is required for at least five consecutive days at a dose of either 100mM in ad libitum drinking water or 0.26 g/kg via oral gavage, to restore normal fear conditioning. Furthermore, stopping BCAA therapy, after 5 days, results in a functional relapse to levels seen in untreated injured animals.”

Significant Findings

“These results suggest the persistence of a functional deficit after TBI, which ongoing BCAA supplementation can successfully treat.”

Limitations

If BCAA therapy is stopped, the neurological hippocampal deficit returns.

Implications for Practice

In this and an earlier research study performed by these researchers, BCAA therapy has been shown to reverse hippocampal cognitive impairment from TBI. This has implications for human TBI therapy with enteral BCAAs. The University of Pennsylvania has applied for a patent to use BCAA therapy for TBI.

Study Title (3)

Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L_arginine decreases contusion size but not behavioral deficits after traumatic brain injury

Journal and Date

Brain Research, July 27, 2011

Brief Summary

Therapeutic effects of AdGDNF and L_arginine post traumatic brain injury were examined. “AdGDNF and L_arginine were injected into cortex immediately post controlled cortical impact. Contusion size was decreased by the combination but not by each treatment alone. Behavioral recovery was not affected.”

Purpose

To contribute to the research database defining TBI therapies.

Sample Population

344 Male Fisher 225 – 300g rats from Charles River Labs

Setting

“Rats were housed within the DePaul University Animal Facility…on a 12:12h light and dark cycle, with food and water available ad libitum. The NIH Guide for Care and Use of Laboratory Animal and Institutional Guidelines were adhered.”

Research Design

Randomly selected/assigned, control/treatment groups, prospective rat study

Theory/Framework

Amino acids supplied to the traumatized brain will affect contusion size

Methods and Intervention

Rats were anesthetized and inflicted with a controlled cortical impact (CCI). Treatment and controls groups of CCI, CCI + saline, CCI + control green fluorescent protein (AdGFP) + saline, CCI + AdGDNF + L_arginine or saline, then Sham only, Sham + AdGDNF + saline and Sham + AdGDNF + L_arginine. AdGFP and AdGDNF viral vectors were injected immediately. Within 30 min. L_arginine or saline “was injected into femoral vein (150mg/kg in sterile 0.9% saline)”. “Behavioral measures of forelimb function were administered on day 0 (pre injury/injections)..then on days 2,4,7,10,14,21 and 28.” “Forelimb coordination.. examined using Foot Fault Test”. Ipsilateral limb use tabulated. Contusion size measured through staining. Staining to detect AdGDNF. GFP expression measured by fluorescent microscope. One-way ANOVA and Fisher’s protected LSD post-hoc test used on contusion volume and GDNF ELISA data. One-way ANOVA and Tukey-Kramer post-hoc test on behavioral data.

Significant Results

Foot Fault Test through Tukey-Kramer post-hoc analysis showed that “AdGDFNF and L_arginine did not affect deficits in or recovery of motor coordination”. “There were no significant differences between all of the injured rats, which indicate that AdGDNF, L_arginine, or the combination of the two did not lessen preferences for the uninjured forelimb.”

Conclusions

“Post-hoc analysis further revealed that rats treated with the combination of AdGDNF and L_arginine post-CCI had significantly smaller contusions than rats that received no treatment post-CCI (32% smaller), rats treated with L_arginine only post-CCI (44% smaller), or rats treated with AdGDNF only post-CCI (44% smaller; all comparisons = p < 0.05).”

Significant Findings

“If neurons are stimulated to complete energy dependent processes post TBI, such as secreting or utilizing a protein …. will result in their death.”

Limitations

AdGDNF and L_arginine do not provide substrate to improve behavioral deficits.

Implications for Practice

AdGDNF and L_arginine may protect humans. AdGNF is “neuroprotective in animal models of stroke, Parkinson’s disease..and spinal cord injury.”

Study Title (4)

N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild TBI in mice

Journal and Date

Journal of Neuroscience Research, May 1, 2010

Brief Summary

“TBI cellular damage may be mediated by the excitatory neurotransmitters, glutamate and aspartate, through N-methyl-D-aspartate (NMDA) receptors.” “Mice preconditioned with NMDA were protected against all motor deficits revealed by footprint test, but not those observed in rotarod tasks”. “Mice showed motor deficits after TBI”, but not cellular damage. Glutamatergic excitotoxicity contributes to trauma severity. NMDA may elicit a neuroprotective mechanism by improving motor behavioral deficits.”

Purpose

To affect motor deficits following TBI

Sample Population

Male CF-1 mice (2-3 months, 30-35g) – UNESC breeding colony

Setting

Six animals/cage with food/water “ad libitum, maintained on a 12-hr light/dark cycle” following NIH Health Guide and Brazilian Society of Neuro & Behavior.

Research Design

Randomly selected, controlled, experimental design using male mice

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

“Animals treated with NMDA (75mg/kg) or vehicle (saline,0.9% NaCl, w/v 24 hr before” diffuse TBI. Sensimotor evaluation 1.5hr, 6 hr, or 24hr after TBI. “Four groups (7-9 mice/group/time = 98 animals)”. “Footprint assessed motor coordination and gaiting”. Rotarod assessed balance. Cellular viability/DNA fragmentation evaluated at 24hr. Footprint and rotarod data analyzed with two- way ANOVA, Fisher’s LSD test for behavioral analysis, footprint by Student’s t- test for dependent variables, p < 0.05.

Intervention

“NMDA dissolved in saline solution, pH to 7.4 with NaOH 1mEq/mol. Animal injected intraperitoneally with a low, nonconvulsant dose of NMDA (75 mg/kg) or vehicle (saline, 0.9% NaCl, w/v) 24hr before cortical trauma injury induction.”

Significant Results

“Sensorimotor behavioral test revealed uncoordinated movements in traumatic mice compared with control mice.” “Preconditioning with NMDA prevented distortion of gait for all parameters of mice that showed deficits.” “Irregular stride length and hindlimb stride observed in mice at 1.5hr after TBI were prevented in preconditioned mice.” “Mice revealed loss of rhythm coordination” via step alternation after TBI “which was prevented by NMDA treatment”. “Animals preconditioned with NMDA and exposed to TBI did not display defects in any of the stride parameters analyzed.” “TBI mice evaluated 1.5hr after TBI were unable to stay on the rotarod,” independent of NMDA or SAL treatment.

Conclusions

“Data showed that neuroprotection evoked by low activiation of the glutamatergic system through NMDA preconditioning was effective against the sensorimotor deficits displayed by mice in a model of diffuse trauma.

Significant Findings

“Protective effect of NMDA … in sensorimotor deficits induced by TBI”

Limitations

NMDA is a receptor; no substrate provided to heal tissue

Implications

That motor deficits can be restored following TBI

Study Title (5)

Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

Journal and Date

PLoS One, February 1, 2014

Brief Summary

“Using two different injury models: either weight drop in mice or fluid percussion injury in rates”, simulating either mild or moderate TBI, “early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with TBI.” Using Y maze for mice and Morris water maze for rats, NAC treatment provided “significant behavioral recovery after injury.”

Purpose

To contribute research to TBI therapies for military personnel

Sample Population

Experiment 1: Male Sprague-Dawley rats between 300 – 400g Experiment 2: Male ICR mice 6-8 wks, 30-40g Sprague-Dawley

Setting

Housed and bred under a 12 hr light/dark cycle and provided with food/water ad libitum.” Guidelines: Instn. Animal Care, Case Western Reserve, NIH Guide Lab

Research Design

Randomly selected, experimental, control, mice fluid percussion injury model

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

Experiment 1: Fluid Percussion Injury Rats, 3 groups: Sham, TBI, TBI-NAC, force of injury 1.82 – 1.95atm. NAC 30min post injury, 50mg/kg ip then q. 24hr for 3 days. Cognitive assessment – Morris water maze- hidden platform, spatial learning and memory. Tested 4 trials per day over 4 days PID 10 13. Morris water maze – probe trail and visible platform.

Experiment 2: Weight Drop Mice, 4 groups: Sham-Vehicle, Sham-Drug (NAC + topiramate), TBI-Vehicle or TBI-Drug (NAC + topiramate). NAC (100mg/kg) + topiramate (30mg/kg) administered ip one hour post injury. Cognitive assessment – 7, 30 days after WD or sham with novel object recognition and the Y maze behavioral tests. SPSS Statistics, one-way or repeated-measures ANOVA and Fisher’s LSD post hoc test, p < 0.05.

Intervention

N-Acetyl-Cysteine in rats, and NAC + Topiramate in saline solution in mice

Significant Results

“Single dose of NAC ameliorates biochemical and histological endpoints” and “multiple doses ameliorate inflammatory sequelae in rat models.” “NAC has antioxidant glutathione (GSH) precursor and anti-inflammatory effects on cytokine cascades and phospholipid metabolism.” “Sulfhydryl group of cysteine serves as a proton donor for antioxidant activity of GSH, rare in foods.”

Conclusions

“The cellular bases of memory and regulation of motivation … may be improved via NAC.” “Despite poor penetration into the CNS, NAC can significantly elevate GSH levels in brain after oxidative stress and GSH deficiency.” “Improved clinical outcomes after early NAC treatment for blast TBI are consistent with the hypothesis that vascular effects of TBI facilitate delivery of NAC to affected sites.”

Significant Findings

“Paper documents the efficacy of NAC in reversing or preventing cognitive abnormalities in rodent models of mild to moderate TBI” this parallels a protocol with blast mTBI in a combat setting including early treatment” w/ NAC/topiramate

Limitations

Studies show this may translate to man in a battlefield blast-induced TBI setting.

Implications for Practice

Often therapies not thought to cross the BBB are tabled. This study shows that amino acids with supposedly limited BBB penetration do reach the brain and can improve outcome.

Study Title (6)

Prolonged continuous intravenous infusion of the dipeptide L-alanine-L- glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe TBI

Journal and Date

Critical Care 2014 18:R139

Brief Summary

“Low plasma glutamine levels are associated with worse clinical outcome” for severe TBI and “optimal glutamine dose to normalize plasma glutamine levels without increasing plasma and cerebral glutamate has not yet been defined”.

Purpose

To determine dosage of glutamine to correct hypoglutaminemia.

Sample Population

“Twelve patient in two separate studies who were comparable presenting with mixed lesions, predominantly consisting of contusion/hemispheric edema. Study 1, two female and four male patients suffering from severe TBI, median age 30 yrs, median BMI 21 kg/m2,” sedated median 13 days. “Study 2, two female and four male patients suffering from severe TBI, median age 28 yrs, median BMI 23 kg/m2,” sedated median 14 days. “Glasgow Outcome Score of 6 at 12 months.”

Setting

Surgical Intensive Care, University Hospital Zuerich, Zuerich, Switzerland

Research Design

Prospective, experimental, 12 TBI Patients anticipated to die within 48 hours

Theory/Framework

Amino acids dosages supplied to the traumatized brain to expedite repair

Methods

“Inclusion criteria: patients suffering from severe TBI reflected by abnormal neurologic status and pathologic neuroradiologic findings were considered eligible when requiring pharmacologic coma.” “Study 1 (n=6), arterial and jugular venous plasma samples drawn at 1,4,12, and 23 hours during the infusion period and after infusion period at 4,12 and 23 hours.” “Study 2 (n=6), plasma arterial and jugular venous samples drawn at predefined time points 1,4,12,24,36,48,60, 72, 84,96,108, and 120 hours, and [drawn] after infusion period at 4,12, 23 and 48 hours.” Indirect Calorimetry performed before and after infusion period.

Intervention

“Study 1: six patients were included to investigate the effects of 0.5g glutamine/kg/ d (Dipeptiven – L+alanine+L+glutamine: 82 mg/100 ml L_alanine and 134.6 mg/ 100ml L_glutamine) continuously infused for 24 hours followed by a 24 hours observation period. In Study 2, a total of six patients were included to investigate the effects of 0.5g glutamine/kg/d (Dipeptiven = :_alanine_L_glutamine; 82mg L_alanine, 134.6 mg L_glutamine) continuously infused for 5 days followed by a 48 hours observation period.” “Dunn’s multiple comparison test, ANOVA,p <0.05.

Significant Results

“Continuous L_alanine_L_glutamine infusion significantly increased plasma and cerebral glutamine and alanine levels (sustained) during the 5 day infusion phase. Plasma glutamate remained unchanged and cerebral glutamate was decreased without any signs of cerebral impairment.”

Conclusions

“High dose L_alanine_L_glutamine infusion (0.75 g/kg/d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamine or signs of potential glutamate-mediated cerebral injury.”

Significant Findings

“Urea and ammonia were significantly increased WNL w/o organ dysfunction.”

Limitations

Optimal dosage not yet determined. Condition improvement not measured.

Implications

Glutamate infusion can be given without deleterious effects to normalize levels.

Study Title (7)

Role of extracellular glutamate measured by cerebral micro dialysis in severe traumatic brain injury

Journal and Date

Journal of Neurosurgery, September 2010

Brief Summary

“High glutamate levels are present in a substantial number of patients, and patterns of glutamate level changes are predictive of patient outcome.”

Purpose

“The present study was to evaluate glutamate levels in TBI, analyzing the factors affecting them and determine their prognostic value.

Sample Population

“Inclusion criteria: a blunt mechanism of head trauma, a GCS score LE 8 on presentation or w/n 48 hrs injury. Exclusion criteria included a penetrating head injury, a presentation GCS score of 3, and fixed, dilated pupils.” 165 patients.

Setting

Ben Taub General Hospital (Level I trauma center) in Houston, Texas (200-2007). Baylor Institutional Review Board approved. NICU, standard protocol.

Research Design

Prospective study, TBI Level 1 165 patients inclusion/exclusion criteria

Theory/ Framework

Consider TBI glutamate levels as related to MABP (mean arterial blood pressure), ICP (intracranial pressure), PO2 or SjvO2 (Jugular venous O2 saturation).

Methods

CT scan, treatable mass to OR, ventriculostomy catheter to monitor ICP, brain tissue PO2 monitor and SjvO2 monitor inserted ICU. Patients intubated/sedated. Head of bed elevated 30 degrees. Pts kept euvolemic, isothermic, feeding 24 hrs post admission. Fluid replacement/vasopressors PRN. ICP > 20 mm Hg treated with ventricluar drainage of CSF, mannitol and mild hyperventilation (PaCO2: 30-35 mm Hg). Barbiturate coma induced and/or decompressive craniectomy as needed. MABP, ICP, brain tissue PO2, SjvO2 recorded every hour for first 120 hours. Chi- square, Wilcoxon rank-sum, Pearson/Spearman correlation. 2 tailed p <0.05,SPSS

Intervention

Fiberoptic catheter in dominant internal jugular vein (Doppler US), verified by radiograph to measure SjvO2. Miniaturized Clark electrode positioned in cortex, non-necrotic frontotemporal region to measure brain tissue PO2. PO2 levels < 10 mm Hg due to hypotension, high ICP, hypoxemia or anemia treated.

Significant Results

“Glutamate in first 24hrs < 10 umol/L in 31 pts. (18.8%), between 10 and 20 umol/L in 58 pts (35.1%), and > 20 umol/L in 76 pts (46.1%). Trend of higher mortality … with glutamate > 20umol/L, however…p= 0.08.” No correlation between early glutamate levels and” initial GCS score or initial ICP.

Conclusions

Two patterns: Pattern 1, glutamate levels normalized. Either “levels initially low and remained low” or “level initially high but decreased over time.” Pattern 2, “glutamate levels tended in to increase over time or remain abnormally elevated.”

Significant Findings

With normalizing glutamate levels (71% of patients) the mortality rate was 17.1%; “41.2% of survivors ultimately achieved a good functional outcome.” With “levels that increase over time or remained abnormally elevated (29% of patients), the mortality rate was 39.6%; 20.7% of survivors had a good functional outcome.”

Limitations

High glutamate levels due to amino acid metabolism necessary for healing. Amino acids may be supplemented to aid in healing irrespective of glutamate levels.

Implications

Glutamate levels can be used as an outcome prognostic value.

Study Title (8)

Dietary Therapy Mitigates Persistent Wake Deficits Caused by Mild TBI

Journal and Date

Science Translational Medicine, December 11, 2013

Brief Summary

Sleep disorders are reported in up to “72% of patients with TBI up to 3 years after injury.” Animal models can “rigorously describe sleep-wake patterns in the chronic setting.” The orexin system may sustain wakefulness. Dietary branched chained amino acids may “alleviate injury-induced deficits in wakefulness.”

Purpose

Amino acids therapies contribute to TBI neurobehavioral consequences.

Sample Population

5 to 7 week old, 20 – 25g, male C57BL/J6 mice from Jackson Labs

Setting

Insulated/soundproof room, 23C, humidity 25%, 12 hr light/dark, 100 lux, free access to food and water. NIH guide, Univ. of Penn. Animal Care Guidelines

Research Design

Randomly, selected, prospective, controlled study, blinded, experimental

Theory/Framework

Consider BCAA as affecting orexin sleep-wake system in TBI

Methods

Two groups of mice: TBI (surgery and fluid percussion (FPI)) and sham (surgery only). FPI mice were anesthetized, 20-ms pulse of saline delivered onto the dura. Pressure 1.4 and 2.1 atm. AccuScan infrared monitoring for 30 days to count beam breaks in 10-s segments to estimate sleep/wakefulness. EEG/EMG signals digitized with Grass Gamma. Subset of mice “(n=7 sham, n=6 TBI, n=6 TBI+BCAA)” “received either BCAA-supplemented water (100mMM) or untreated tap water (control), 3-5ml/day. Baseline recorded day 1, 2, and 5.

Intervention

After Sham or TBI, EEG/EMG recorded Wake, NREM and REM sleep cycles. Polygraphs for 2 hours on day 3 and 3 hours on day 4. Anti-orexin-antibodies coated lateral hypothalamus, visualized with fluorescence to identify orexin neurons. Student’s t-test, one-way ANOVA, Dunnetts post hoc test, p < 0.05.

Significant Results

“Time spent continuously active, was significantly shorter in TBI mice.” Decreased and shortened activity bouts was evident in brain-injured mice. “The total number of transitions between active/inactive bouts was significantly increased after TBI”. “TBI mice spent significantly less time in both the light and dark phases, and more time in NREM sleep.” TBI mice treated with BCAAs showed a partial reversal of changes in wake and NREM states. “Total number of wake-to-sleep transitions was significantly increased in TBI mice compared to sham mice, and BCAA intervention after TBI decreased number of transitions back to sham control levels.” “Wake spectra for TBI mice were significantly lower at the theta frequency range (8-9hz), compared to sham control mice.” “Theta power was restored by BCAA therapy for spectra in the NREM state.” “TBI mice had a shorter latency to sleep compared to sham mice, and this shorter latency was partially restored by BCAA intervention.” “Compared to the sham and TBI + BCAA groups, TBI mice had significantly fewer activated orexin neurons.”

Conclusions

BCAA therapy restores many aspects of wakefulness, including EEG and orexin.

Significant Findings

“Total orexin neuron numbers were not significantly different between groups, indicating that injury primarily affects physiology rather than gross cell loss.”

Limitations

Not a therapeutic human experiment, yet.

Implications

Amino acid therapies highly effective in mice. BCAA therapy patent applied for.

Study Title (9)

Vasopressin for cerebral perfusion pressure management in patients with severe TBI: Preliminary results of a randomized controlled trial

Journal and Date

Journal of Trauma and Acute Care Surgery

Brief Summary

“AfterTBI, catecholamines (CAs) may be needed to maintain adequate cerebral perfusion pressure (CPP), but there are no recommended alternative vasopressor therapies. This is an interim report of the first study to test the hypothesis that arginine vasopressin (AVP) is a safe and effective alternative to CAs for the management of CPP in patients with severe TBI.

Purpose

To contribute to the knowledge base on amino acid vasopressor TBI therapies.

Sample Population

“Since 2008, all TBI patients requiring ICP monitoring at this Level 1 trauma center have been eligible for a randomized trial to receive either CA or AVP if vasopressors were required to maintain CPP greater than 60 mm Hg.” Minors, pregnant women and incarcerated individuals were excluded.

Setting

University of Miami/Jackson Memorial Hospital, Ryder Trauma Center

Research Design

“Single-institution, prospective, open-label, randomized, controlled clinical trial.”

Theory/Framework

Considering use of arginine as an alternative vasopressor therapy

Methods

TBI patients randomized to CA (control) or AVP for CPP management but only receive vasopressors if medically indicated. Stabilized in resuscitation. Transferred to neurosurgery or Trauma ICU if polytrauma. Switching vasopressors allowed. Deaths IRB reviewed. GCS, SBP, DBP, MAP, HR, CPP, ICP, fluids and meds data.

Intervention

“Treatment protocols: if CPP > 60mmg Hg no vasopressors required. If CPP < 60 mm Hg, ICP was < 20 mm Hg, and systolic BP < 90 mm Hg, then resuscitation was performed with fluid/blood products.” If pt. resuscitated “with CPP < 60 mm Hg and/or ICP < 20 mm Hg, then vasopressors were initiated to raise CPP < 60 mm Hg and systolic BP > 90 mm Hg.” AVP dosage was 1.2 U/h, increased 4 U/h.

Significant Results

To date, 96 patients have been randomized. Demographics, vital signs, and lab values were similar. As treated, 60 required no vasopressors, were least severe, had best outcomes. 23 patients received CS (70% levophed, 22% dopamine, 9% phenylephrine) and 12 patients received AVP. The two vasopressor groups had worse Injury Severity Score (ISS) and fluid requirements on ICU Day 1 in the AVP versus the CA group (p < 0.05) before treatment.” “Adverse events were not increased with AVP versus CA. Trends favored AVP versus CA, but no differences were statistically significant.. and there was no difference in mortality rates.”

Conclusions

“Preliminary results suggest that AVP is a safe/effective alternative to CA for the management of CPP after TBI and support the continued investigation and use of AVP when vasopressors are required for CPP management in TBI patients.”

Significant Outcomes

“AVP is effective for patients in septic shock, refractory cardiac arrest, and animal hemorrhagic shock models, showing that AVP is effective in combination with fluid resuscitation.” This “study reports a novel off-label indication for AVP.”

Limitations

Multi trauma center study desirable. Not evaluating arginine as healing substrate

Implications

A human study showing efficacy of AVP as a vasopressor therapy in human TBI.

Study Title (10)

Open-Label Randomized Trial of the Safety and Efficacy of a Single Dose Conivaptan to Raise Serum Sodium in Patients with TBI

Journal and Date

Neurocritical Care, 2011

Brief Summary

This study evaluated the use of conivaptan in TBI patients who had normal sodium levels to determine efficacy and whether intervention could reduce ICP. The study found that no adverse events occurred and ICP was reduced within 4h.

Purpose

To determine whether this arginine-vasopressin receptor antagonist is safe in normonatremic patient with TBI and could reduce ICP with a single dose.

Sample Population

216 patient assessed for eligibility, 10 met inclusion criteria.

Setting

Harborview Medical Center, Level I trauma center, Seattle, Washington. “Study approved by Human Subject Division Review Board of University of Washington.”

Research Design

“Open-label, randomized, controlled trial enrolling 10 subjects within 24h of severe TBI to receive single 20mg dose of conivaptan (n=5) or usual care (n=5).”

Theory/Framework

An arginine-vasopressin receptor antagonist could reduce ICP in TBI.

Methods

Admission criteria included age GE 18, ICU admission, severe TBI as defined by GCS of LE 8, ICP monitoring required, supplemental sodium needed to “raise to 10 mEq/l higher than admission to reduce cerebral edema and/or ICP.” A number of exclusion criteria existed including polytrauma. “Patients randomized to receive conivaptan in addition to usual care (n=5) or usual care alone (n=5). End point if serum sodium above target goal range or any drug-related adverse events. Seconday end points, mean serum Na, Na load in first 48 hr, mean ICP values, change in ICP, CPP. Urine volume measured in 4 h intervals during first 48h.

Intervention

Open-label administration. Conivaptan single dose of 20mg, mixed with 100ml of 5% dextrose in water, and infused over 30 min. Sodium assessment q. 4h.

Significant Results

Statistical methods included Student’s t-test, chi-square, linear mixed effects models to compare ICP with serum sodium, 2 sided, sig of 0.05. STATA vers 11. While further studies are required, conivaptan appears to be safe and effective at lowering ICP. Previous ICP therapies including “mannitol and hypertonic saline solutions elevate the osmolarity with in the cerebral vasculature and increase fluid movement across the BBB and into the capillary system.”

Conclusions

“Data suggest that a single dose of conivaptan is safe in non-hyponatremic patients with severe TBI for .. the purpose of ICP control. Conivaptan caused an increase in serum sodium within 4 h of administration with a concomitant significant reduction in ICP without adverse effects.” “Achieves ICP control.”

Significant Findings

“The observation that conivaptan has significant effects on ICP associated with a steep change in sodium level is important.” This fall in ICP is within 3-5 h.

Limitations

Avoid Conivaptan “in the presence of hypovolemia” since associated with diuresis.

Implications

An arginine product is effective at controlling human ICP with a single dose.

References – Primary Articles:

1. Elkind JA, Lim MM, Johnson BN, Palmer CP, Putnam BJ, Kirschen MP, Cohen AS. Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury. Front Neurol. 2015 Mar 30;6:73. doi: 10.3389/fneur.2015.00073. eCollection 2015. PMID: 25870584 Free PMC Article

2. Senol N, Naziroglu M, Yuruker V. N-Acetylcysteine and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats. Neurochemical Research, 2014 Apr, 39:4, pp 685-692. doi: 10.1007/ S11064-014-1255-9. PMID: 24519543

3. Degeorge ML, Marlowe D, Werner E, Soderstrom KE, Stock M, Mueller A, Bohn MC, Kozlowski DA. Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L-arginine decreases contusion size but not behavioral deficits after traumatic brain injury. Brain Res. 2011 Jul 27;1403:45-56. doi: 10.1016/j.brainres. 2011.05.058. Epub 2011 Jun 2. PMID: 21672665 Free PMC Article

4. Costa T, Constantino LC, Mendonça BP, Pereira JG, Herculano B, Tasca CI, Boeck CR. J. N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild traumatic brain injury in mice. Neurosci Res. 2010 May 1;88(6): 1329-37. doi: 10.1002/jnr.22300. PMID: 19998488

5. Eakin K, Baratz-Goldstein R, Pick CG, Zindel O, Balaban CD, Hoffer ME, Lockwood M, Miller J, Hoffer BJ. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One. 2014 Apr 16;9(4):e90617. doi: 10.1371/journal.pone.0090617. eCollection 2014. PMID: 24740427 Free PMC Article

6. Nägeli M, Fasshauer M, Sommerfeld J, Fendel A, Brandi G, Stover JF. Prolonged continuous intravenous infusion of the dipeptide L-alanine- L- glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe traumatic brain injury. Crit Care. 2014 Jul 2;18(4):R139. doi: 10.1186/ cc13962. PMID: 24992948

7. Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010 Sep;113(3):564-70. doi: 10.3171/2009.12.JNS09689. PMID: 20113156 Free PMC Article

8. Lim MM1, Elkind J, Xiong G, Galante R, Zhu J, Zhang L, Lian J, Rodin J, Kuzma NN, Pack AI, Cohen AS. Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci Transl Med. 2013 Dec 11;5(215):215ra173. doi: 10.1126/ scitranslmed.3007092. PMID: 24337480

9. Van Haren RM, Thorson CM, Ogilvie MP, Valle EJ, Guarch GA, Jouria JA, Busko AM, Harris LT, Bullock, MR, Jagid JR, Livingstone AS, Proctor KG. J Vasopressin for cerebral perfusion pressure management in patients with severe traumatic brain injury: preliminary results of a randomized controlled trial. Trauma Acute Care Surg. 2013 Dec; 75(6):1024-30; discussion 1030. doi: 10.1097/TA.0b013e3182a99d48. PMID: 2425667

10. Galton C1, Deem S, Yanez ND, Souter M, Chesnut R, Dagal A, Treggiari M. Open- label randomized trial of the safety and efficacy of a single dose conivaptan to raise serum sodium in patients with traumatic brain injury. Neurocrit Care. 2011 Jun;14(3): 354-60. doi: 10.1007/s12028-011-9525-8. PMID: 21409494

References – Review Articles:

11. Institute of Medicine, 2011. Nutritional and Traumatic Brain Injury: Improving Outcomes in Military Personnel. A shortened version of this IOM book can be found on the website nationalacademies.org.

12. Scrimgeour, AG, Condlin ML. Nutritional Treatment for Traumatic Brain Injury. Journal of Neurotrauma 31.11, Jun 1, 2014: 989-99.

 

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.

Fish Oil (DHA – omega 3) Therapy for TBI and Concussion: A Literature Review

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Fish Oil and Concussion: A Case Study and Review

 

Case Study: A 14 y/o female, club soccer player suffered concussion. She continued to play through two full-length soccer games. In the days following, she suffered headaches and bright flashes of light in both visual fields. Loud sounds exacerbated the pain. She experienced complete exhaustion, lack of concentration, and difficulty sleeping. Sports activities caused headaches. She missed school due to the chronic pain, causing her grades to drop. As months passed, she discontinued sports and “lost hope in life”. Having been diagnosed with concussion, she visited multiple physicians who initiated various therapies without resolve. To avoid social exclusion, she did not discuss the pain publicly. The following year, she began taking 500mg fish oil supplements of docosahexanoic acid (DHA). Over the next month, the headaches were alleviated, allowing her to return to previous school and sports activities.

Discussion: Concussion and traumatic brain injury(TBI) cause approximately 52,000 deaths, 220 hospitalizations, and 85,000 permanent cases of debilitation each year in the U.S.. Concussion has seen a 4.2 fold increase in cases since 1998 (Barrett et.al, 2014). Symptoms include loss of consciousness, headache, a fogginess, light sensitivity and sleep disturbances for typically 7-10 days after injury. Symptoms may persist for months or longer. (Barrett EC, et.al. 2014). Laboratory rodent experiments show that nerve axonal injury is a progressive event which leads to the swelling and disconnect of the axon membrane in hours to days following TBI. The injury causes a lack of transport and communication across axonal membranes, ultimately leading to cell death (Mills JD, et.al., 2011). The societal impact of concussion is staggering given it’s excessive financial cost and ability to cause long term mental disease.

Fish oil contains omega-3 fatty acids such as docoashexanoic acid (DHA) and eicosapentanoic acid (EPA). This paper explores the current literature evaluating docosahexanoic acid (DHA) as a potential therapy for TBI. Omega-3 fatty acids, most significantly DHA, comprise 60% of brain tissue (Crawford, et al, 1993). An improved understanding of the omega-3 fatty acid nutritional requirements such as DHA, has improved concussion outlooks (Mills JD, et.al., 2011). DHA is essential for maintaining membrane fluidity, thereby affecting the speed of neuronal transmission. Previous laboratory rodent studies have demonstrated the neurological benefits of DHA. More recently, military studies have shown the neurologic benefits of DHA in humans. When

brain tissue is damaged, supplying adequate levels of docosahexanoic acid can be a protective and restorative mechanism for neuronal tissue (Hasadri L, et.al., 2013).

Rodent Neuroprotective DHA findings:

Rodent studies significantly advanced brain trauma therapy in 2006, when a single intravenous dose of DHA was found to reduce inflammatory markers and improve neuron survival (King VR, 2006). In 2008, Drs. Wan-Ling Chung, Jen-Jui Chen, and Hui-Min Su of the Department of Physiology, National Taiwan University College of Medicine in Taipei 100, Taiwan sought to determine whether reference and working memory could be enhanced with DHA supplementation in male rats previously DHA deficient. They fed pups divided into four groups either a normal diet, an eicosapentanoic acid (EPA) supplemented diet, a DHA supplemented diet, or an omega-3 deficient diet. At 140 days after birth, they assessed memory in the rats, through use of a Morris Maze. The rats found the location of the submerged platform in a working memory test and remembered the location of the platform in a reference memory test. The DHA deficient rats showed a significantly poorer memories which were partially improved with DHA supplementation. Rats receiving supplementation throughout brain development and adulthood resulted in a significant enhancement of both memories (Chung, 2008). The hippocampus showed a greater accumulation of DHA.

In evaluation of this study based upon the Quality Criteria Checklist for Primary Research in Non-Human Subjects, this study does not discuss the number of rats in study. The rat selection appears to be free of bias having been obtained from Charles River Laboratories in Taiwan. The criteria appear to have been applied evenly with relevant characteristics being described and analyzed through tissue samples in the lab. Controls were used. Data and statistical analysis appear to be valid, but study groups are not elaborated upon. Interventions were described in detail as to diets and the outcomes clearly defined. Observations and measurements appear to be based on standard, valid, and reliable data. At some points, there appears to be confusion on which type of memory is being measured. They had two goals in determining whether supplementation could revive memory in previously deficient rats and if recovery was brain region specific. They received positive results with both hypotheses. The importance of this study, in the eventual development of DHA as a therapy, is that improvements in rodent neurocognitive abilities are established.

 

In 2011, two researchers, Dr. Julian Bailes and Dr. J.D. Mills from West Virginia University School of Medicine in Morgantown, West Virginia found that DHA supplementation significantly ameliorated secondary mechanisms of injury and reduced the number of damaged axons in 40 Sprague-Dewey male rats. They randomly selected four groups of 10 rats. One group served as a sham concussion group. A second group received a concussion but no fish oil. The third group received 6mg/kg/day of DHA and a fourth group, 24 mg/kg/day of DHA. DHA was neuroprotective in both the 6mg/kg/day and 24 mg/kg/day populations when administered for 30 days post concussion. The neurons were labeled for damage. The 6mg/kg/day and 24 mg/day groups showed 6.2 +/- 11.4 and 7.7 +/- 14.4 neurons labeled for damage, respectively. This labeling nearly matched the control sham concussion group (Mills, 2011).

In analyzing the results from Bailes and Mills, according to study criteria on the Qualify Criteria Checklist for Primary Research of Non-Human Subjects, the selection of study subjects were not free from bias in that only males rats were used. The study groups appear to be comparable in that random, concurrent controls were utilized given the sham injured, injured supplemented, 6mg/kg/day, and 24 mg/kg/day study groups. Protocol and context were described in detail. The intensity, duration, and treatment were sufficient to produce a meaningful effect and the data appeared to be free from bias and similarly assessed. Key outcomes and nutrition related data were well described and measured with several different markers. Data was based upon reliable procedures/testing and the level of precision was p < 0.05. Measurements were conducted consistently among the groups and the study reported a 96% reduction of axonal injury after DHA supplementation of only 6 mg/kg/day. While researchers may increase the size of this cohort to improve additional studies, the degree of positive results are impressive.

The neuronal tissue in the brain extends down the brainstem into the spinal cord.
Spinal cord injuries (SCI) have long caused debilitating injury to the sensory and motor neurons below the injury site. In 2013, researchers at Loma Linda University found that DHA protected and restored neurons, resulting in significant improvement in the motor

and sensory tract functions destroyed following spinal cord injury (Figueroa, 2013).
DHA supplemented for 8 weeks in female Sprague-Dawley rats mediated the chronic pain present with SCI. They found that our Western diet may be hindering recovery from SCI, and that chronic DHA deficiency is associated with dysfunction following SCI (Figueroa, 2013). These research studies report that dietary prophylaxis with DHA results in distinctive improvements of nerve function that may facilitate functional recovery after SCI (Figueroa J, et.al., 2013).

Human DHA Neuroprotective Findings:

In 1997, the U.S. Food and Drug Administration confirmed that fish oil at levels up to 3 g/day were generally recognized as safe in the Federal Registry. At the same time, the FDA determined that fish oil up to 4 g/day was safe for cardiovascular therapy (FDA, 1997). In 1998, depression rates were found to be 50 times higher in countries with little seafood consumption (Hibbeln, 1998).

By 2005, Daily Reference Intakes did not yet provide for an Recommended Daily Allowance for DHA. Fish oil in the quality of 2g/d were shown to reduce suicidal tendencies, depression, and the perception of stress (Hallahan B, et.al., 2007). In 2010, the U.S. Dietary Guidelines added increased seafood consumption to its recommendations.

In 2011, the Institute of Medicine (IOM) published an extensive report entitled “Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel” which reviewed current literature on DHA and TBI. They reported that 80 percent of the fatty acids consumed in the U.S. were omega-6 or linoleic acids at a rate of 17g/day, and that while DHA is synthesized from alpha linoleic acid, only low amounts are produced (IOM, 2011). In animal studies, DHA was shown to have anti- inflammatory and neuroprotective activities in the brain and retina (IOM, 2011). Human studies showed that TBI patients would benefit by an inflammation reduction within 60 minutes of infusion (IOM, 2011). The IOM recommendation requests that more animal studies and human clinical trials be conducted. The conclusions further state that while intravenous fish oil formulations are available in Europe they have not yet been approved by the FDA in the U.S. The IOM recommends the early phase of severe TBI be provided with continuous enteral feeding with a formula containing fish oil (IOM, 2011).

 

This review is most significant in that is was formulated by the Institute of Medicine. While this is not original research, it is based upon original research of many research efforts which have received a positive rating from the IOM in that research reviewed has addressed issues of inclusion/exclusion bias, generalizability, and data collection and analysis. It is disappointing that 5 years post IOM report, the American Medical Society has not recommended the use of fish oil for TBI and the FDA has not published a position on the safety and efficacy of fish oil and TBI updating their 1997 declaration. While there have been remarkable case studies published demonstrating the efficacy of fish oil in severe TBI incidents, TBI is generally not treated with fish oil in the U.S..

Given the IOM call for additional human studies, a markedly higher rate of suicide among individuals who have suffered TBI as compared with the normal population has been demonstrated (Nowrangi, 2014). Dr. Michael D. Lewis and Dr. Joseph R. Hibbein of the Uniformed Services University in Bethesda, Maryland sought to determine if deficiencies in DHA were associated with an increased risk of suicide among a large, random sample of military personnel (Lewis, 2011). In a retrospective study they assayed serum samples from 800 military personnel who had committed suicide with 800 controls randomly matched for age, collection date, sex, rank and year of incident with sera within 12 months of their matched case (Lewis, 2011). Samples were assayed for DHA composition by robotic direct methylation coupled with fast gas-liquid chromatography to account for possible degradation. Researchers found that there was no difference when comparing female controls with cases, however there was a 62% greater risk of suicide death among men with lower serum DHA levels (Lewis, 2011).

In evaluating this study by the Quality Research Checklist for Primary Research, this study was not free from bias in that more men committed suicide than women. Given the military’s high availability of data, inclusion criteria were specifically matched with controls. Criteria appeared to be applied equally. Health and demographics were carefully described. Subjects appear to be a representative sample of the relevant population. The population is some what unique in being all military. Study groups were remarkably comparable given the military’s high availability of data. This study was randomized with 800 cases and 800 controls. The distribution of disease status was similar across the study groups. Concurrent controls were utilized. This was a case control study and there was blind comparison. There were no interventions or therapeutic regimens. All procedures were compared in detail. An exposure factor may have been the age of the serum, but the military was careful to utilize cases and control serum with similar dates and ages to alleviate discrepancies. Outcomes were clearly defined, and measurements valid and reliable. State-of-the-art equipment and statistical analysis were available to the military. Their primary hypotheses of whether suicide would be related to lower DHA levels was confirmed.

 

In this military study, nutrition measures were appropriate to outcome. Observations and measurements were based upon standard, valid, and reliable data collection instruments/tests/procedures. Precision varied from p < 0.01 to p < 0.07 (Lewis, 2011). Other factors were accounted for and the measurements were not consistent across groups in that DHA levels did not vary among women. Overall, this study presents sufficient information to form a positive correlation between suicidal tendencies and low levels of DHA. This study does not show that DHA will prevent suicide, however in using 1600 subjects, randomized and blinded this is an important report. The psychological benefit of a diet including DHA is confirmed.

In 2013, the American Medical Society for Sports Medicine (AMSSM) published a position statement on concussions. The purpose of their statement was to provide physicians with a practice summary to manage sports concussions, and to identify the current level of information including knowledge gaps needing additional research. They expressed the need for competent physicians experienced with concussion management to provide care and issue return-to-play decisions. They defined concussion or mild TBI as a disturbance of brain function involving a complex pathophysiological process which is generally self-limited and considered a less severe brain injury (Harmon, 2013). Researchers estimated that 3.8 million concussions occur in the U.S. per year with half going unreported (Harmon, 2013). They expressed concern for repeat injuries prior to initial recovery, causing severe metabolic changes in brain tissue.

The AMSSM discussed diagnosis of concussion, evaluation, and management by a knowledgable healthcare provider. They indicated the sensitivity of baseline neurocognitive testing by health care professionals. However, the AMSSM states that most concussions can be managed without neurocognitive testing. Academic accommodations such as reduced workload and rest were recommended for students.

Concern was expressed for long term disease management and “neurological sequelae” (Harmon, 2013). Additional studies were requested to determine the long term effects of concussion. In preventing concussion, fair rules of play, helmets and legislative efforts were recommended (Harmon, 2013) In terms of future directions, the AMSSM requests further research in neurocognitive testing, assessment tools, improved imaging tools, and the identification of additional biological markers to provide new insight. (Harmon, 2013).

Given the publication of the IOM report of 2011 calling for the use of fish oil as treatment for acute TBI, the lack of AMSSM recommendations for research and clinical application of these therapeutics is disappointing. Instead of treating the condition, the AMSSM appears focused on improving diagnosis and imaging tools. Further, the AMSSM discounts neurocognitive testing. By 2013 baseline neurocognitive testing has become standard in many school and universities across the nation, whereby individual baseline test are compared with post concussion tests to determine return-to-play. These testing systems are managed by school and university athletic trainers, and have proved critical for concussion management. A more treatment oriented AMSSM report would have addressed the proficiency of the current level of neurocognitive testing and recommended additional usage. The purpose of this report was to identify knowledge gaps. Given the current evidence on DHA it seems important to present the current research findings, and to issue a call to the medical community for additional clinical testing. Hopefully, the grave risk of liability in the U.S. has not thwarted our ability to potentially ameliorate 96% of brain trauma.

In 2013, Dr. Linda Hasadri, et.al. of the Mayo Clinic’s Department of Laboratory Medicine and Pathology, Rochester, Minnesota published a review of TBI DHA studies in the Journal of Neurotrauma. Her team reported that TBI is a global health risk and that nutritional interventions, such DHA, may provide a unique opportunity to repair brain tissue (Hasadri, 2013). While there have not been results of clinical trials evaluating the treatment of TBI with omega-3 fatty acids published, both animal and human studies have provided positive results (Hasadri, 2013). Chronic head injury may result in long term neurological disease including Alzheimer’s, Parkinson’s Disease, Post Traumatic Stress Disease, neurocognitive deficits, depression, and an inability to function (Hasadri, 2013). To improve outcomes, omega-3 fatty acids, such as DHA, may be obtained from a diet heavy in cold water fish, algae and krill (Hasadri, 2013), free range meat, cage free eggs, and fortified infant formula.

 

The Hasadri teams describes DHA as the longest and most unsaturated fatty acid. DHA provides a tremendously flexible and versatile structure, playing a significant role in the function of the neural cell membrane, retina, and sodium potassium pump (Hasadri, 2013). Pro-apoptotic proteins are down regulated and anti-apoptotic proteins are up-regulated with therapy (Hasadri, 2013). Chronic deprivation of DHA leads to learning and memory deficits, and decreased function of cholinergic and dopamine pathways. Risks may exist in that DHA has an oxidation potential that could create a carcinogenic substance. A fishy odor and rancidity are possible. In addition, there is a high risk of exposure to mercury and environmental toxins, although the benefits currently outweigh the risks (Hasadri, 2013). The research team concludes that DHA restores cellular energetics, reduces oxidative stress and inflammation, repairs cellular damage, and mitigates the activation of apoptotic processes after TBI (Hasadri, 2013). They conclude that DHA may provide a unique, well tolerated, easy to administer opportunity to treat TBI (Hasadri, 2013). This is an elegant summary of current research which additionally discusses the opportunity to inexpensively and practically reduce the societal impact of TBI with fish oil.

In 2014, The U.S. Food and Drug Administration (FDA) published a consumer health information publication entitled “Can a Dietary Supplement Treat a Concussion? No!”. This short report was apparently issued as a warning to companies and individuals.
The FDA reports that there is no scientific evidence that any supplements are safe and effective for preventing, treating or healing concussion (FDA, 2014). They state that no supplements exist that might allow athletes to return-to-play sooner than they are ready. They address the important need for patients to receive care from medical professions, that repeat injuries have a cumulative effect, and there may be substantial long-term neurological impact of concussions (FDA, 2014). The FDA sent warnings to physicians and companies selling products containing DHA supplements advertised as being beneficial for concussions. The FDA is calling these claims false and threatening legal action against any physician or company selling nutrients for this purpose.

In analyzing this report issued August, 2014 by the Federal Drug Administration, one wonders why the FDA failed to educate the consumer about rodent and human studies of distinguished researchers over the past decade, and more importantly, human research studies from the Institute of Medicine in 2011 and the U.S. Military calling for additional research and the use of fish oil with acute TBI. Instead, the FDA choose to

 

keep the consumer uneducated. In addition, they are thwarting attempts by physicians to further research and development of the important therapeutic use of a fatty acid which the FDA declared safe 20 years ago. It seems that the appropriate leadership role of the FDA should include educating physicians and consumers on the current status of fish oil research and promoting additional research for the benefit of the public it serves.

It is estimated that the cost of development and approval of a new drug is approximately $2.6B (Tufts, 2014), a percentage of which are fees collected by FDA from pharmaceutical companies. In issuing this negative report, perhaps the FDA is attempting to halt inexpensive public solutions from developing, thus allowing time for pharmaceutical companies to test prescription fish oil products requiring FDA approval and bringing profits to the FDA. As consumers await the actions of government bureaucracy, 3.8M consumers suffer concussion annually (AMSSM, 2013). In the meantime, consumers’ lack of information will cause them to bear the psychological and physiological burden of concussions, the long term neurological sequelae, increased health care premiums, and ultimately, the increased cost of purchasing FDA approved, prescription fish oil.

In 2014, the Academy of Nutrition and Dietetics issued a position paper on “Dietary Fatty Acids for Healthy Adults” they noted that Registered Dietitians are “uniquely positioned” to conduct research into dietary recommendations on fatty acids. The paper discusses fatty acid classifications and the need for 20-35% of the diet to be comprised of a variety of fatty acids. They discuss the structural importance of the double bonds in the omega-3 polyunsaturated fatty acids, and present a table describing the intake allowances recommended by the various agencies. The paper discusses the sources of DHA as being from fatty fish, seafood, salmon, sardines, tuna, herring, trout, seal meat, and marine or algal sources (AND, 2014). Importantly they state that while DHA has not been labeled an essential oil, because of the potential conversion of alpha- linolenic acid (ALA) to DHA, less than 1% of ALA reliably converts to DHA (Davis, 2003)(Burdge, 2004). DHA modulates inflammation and is neuroprotective. Supplements are made from fish oils such as anchovy, salmon, cod liver, krill and squid oils (AND, 2014). Up to 3g/day was generally recognized as safe by the FDA in 1997. Vegetarian sources of algae are available and genetically engineered supplements are being developed. The Academy’s position states the mean daily intake of DHA was

 

80mg for men and 60mg for women (AND, 2014) far below the recommended research dosages. Multiple agencies, including the American Psychiatric Association, do recommend fish twice a week for an average 450 to 500 mg of EPA and DHA per day (AND, 2014), stating that lower levels of DHA have been observed in individuals with cognitive decline and Alzheimer’s Disease (AND, 2014). The Academy’s Evidence Analysis Library examined 14 studies, whereupon 6 of these studies showed DHA demonstrated a decreased risk of cognitive decline (AND, 2014).

The Academy of Nutrition and Dietetics could be a controlling influence in the advancement of fatty acids as a major neurological and cardiovascular protectant by promoting research and dietary recommendations to dietitians to encompass this safe and effective food supplement in the scope of their practice. Thus far, only the American Psychiatric Association is willing to recommend 450mg to 500mg per day of DHA. The American Medical Society currently lacks the scope and educational background. However, once supplements become regulated, the pharmaceutical companies and physicians will control their benefits through less nutrient based drug compounds. Consumer will loose access to these nutrients and the cost of nutrient based drug compounds will skyrocket. The opportunity for dietitians to control fish oil and other supplements in nutrient form exists now. Consumers will reap the health benefits of pure biochemistry based nutrient supplements vs. pharmaceutical drug, non- nutrient interventions, and the scope of dietitians to heal through biochemistry will expand exponentially.

The military is seeing the benefits of fish oil to heal their traumatized soldiers. In the November 2014 issue of Military Medicine, Julian Bailes MD and Vimal Patel PhD report that “our knowledge of the pathophysiology of cerebral concussion has undertaken significant advances in the last decade.” Military have a higher risk of repetitive injury due to explosive devices, resulting in a “unprecedented rate of non- penetrating head injury” (Bailes and Patel, 2014). Mitigation or prevention can be accomplished through DHA improving the neuroprotective effect when high doses (40 mg/kg) are given (Bailes and Patel, 2014).

In this review, Bailes and Patel explain the more recently recognized damage caused by TBI including the build up of tau protein, neurofibrillary tangles, and the long term development of chronic traumatic encephalopathy (Bailes and Patel, 2014). They describe how the highly flexible, long chain DHA fatty acid creates thin phospholipids

 

which pack well within the cell membrane, creating a more permeable phospholipid more suitable to membrane proteins, transport, signaling, and enzymes. They re-iterate that DHA decreases b-amyloid plaque buildup, reduces neuronal apoptosis, and may act as a prophylactic against cerebral concussion (Bailes and Patel, 2014). They recognize that the U.S. FDA designated DHA as Generally Recognized as Safe in 1997 (FDA, 1997).

In concluding, Bailes and Patel discuss the availability of DHA from fatty fish or algae sources and the potential presence of mercury. They recognize that given the safety profile, general health benefits, purity, availability and affordability of DHA, both our athletes and military populations, with high exposure to repetitive brain impacts, are at risk without adequate DHA (Bailes and Patel, 2014).

Conclusion:

DHA has been demonstrated to have a role in TBI recovery. The current state of DHA literature is primarily based upon animal models although, the military has initiated human studies. There are several clinical trials of DHA for TBI in progress. DHA has a strong safety profile and is a promising therapy. Intake recommendations range from 250 mg/d to 500 mg/d while current dietary recommendations are less than half that at 90-120mg/d (Barrett, 2014). Rat studies have shown efficacy at a mean human intake of 387 mg/d of DHA (Barrett EC, 2014). Given these studies, timing would be excellent for AND, AMA, and FDA to evaluate adequate DHA intake levels and educate their professionals as to the benefits of DHA. Legal agencies might lessen the liability risk of

 

initiating TBI therapy. Organizational and legislative agencies entrusted with health care planning and protection might better serve the public by increasing awareness and availability of these beneficial findings. Our military, athletes, and scholars would benefit most from this information to protect their brain function, thereby decreasing the mental healthcare burden placed upon society in terms of excessive costs and loss of lives.

References:
Bailes JE, Mills JD. (2010). Docosahexaenoic acid reduces traumatic axonal injury in a

rodent head injury model. J. Neurotrauma 27, 1617-1624.

Bailes JE, Patel V, (2014). The potential for DHA to mitigate mild traumatic brain injury. Mil Med 2014 Nov;179(11 Suppl):112-6. doi: 10.7205/MILMED-D-14-00139.

Barrett EC, McBurney MI, Ciappio ED. w-3 fatty acid supplementation as a potential therapeutic aid for the recovery from mild traumatic brain injury/concussion. Adv Nutr. 2014 May 14;5(3):268-77. doi: 10.3945/an.113.005280. Print 2014 May.

Burdge G. Alpha-linolenic acid metabolism in men and women: Nutritional and biological implications. Curr Opin Clin Nutr Metab Care. 2004;7(2):137-144.

Crawford MA. (1993). The role of essential fatty acids in neural development: Implications for perinatal nutrition. Am J Clin Nutr 57, 703S-09S; discussion 09S-10S.

Davis BC, Kris-Etherton PM. Achieving optimal essential fatty acid status in vegetarians: Current knowledge and practical implications. Am J Clin Nutr. 2003;78(3 suppl):640S-646S.
FDA Substances affirmed as generally recognized as safe: Menhaden oil. Final Rule: Federal Registry, 1997, 30751-30757.

Figueroa JD, Cordero K, Lian MS, De Leon M. Dietary omega-3 polyunsaturated fatty acids improve the neurolipidome and restore the DHA status while promoting functional recovery after experimental spinal cord injury. J Neurotrauma. 2013 May 15;30(10):853- 68. doi: 10.1089/neu.2013.2718.

 

Figueroa JD, Cordero K, Serrano-Illan M, Almeyda A, Baldeosingh K, Almaguel FG, De Leon M. Metabolomics uncovers dietary omega-3 fatty acid-dervied metabolites implicated in anti-nociceptive response after experimental spinal cord injury. Neuroscience 2013;255-1-18. doi: 10.1016/j.neuroscience.2013.09.012. Epub 2013 Sep 14.

Hallahan B, Hiebbeln JR, Davis JM, Garland MR: Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br. J Psychiatry 2007; 190: 118-22.

Harmon KG, Drezner JA, Gammons M, Guskiewicz KM, Halstead M, Herring SA, Kutcher JS, Pana A, Putukian M, Roberts WO. (2013). American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med 2013 Jan; 47(1);15-26. doi: 10.1136/bjsports-2012-091941.

Hasadri L, Wang BH, Lee JV, Erdman JW, Liano DA, Barbey AK, Wszalek T, Sharrock MF, Wang HJ. Omega-3 fatty acids as a putative treatment for traumatic brain injury. J Neurotrauma. 2013 Jun 1;30(11):897-906.doi:10.1089/neu.2012.2672.Epub 2013 Jun 5.

Hibbeln JR: Fish consumption and major depression. Lancet 1998; 351(9110): 1213.

Huang WL, King VR, Curran OE, et al. (2007). A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain 130, 3004-3019.

Institute of Medicine, April 22, 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

King VR, Huang WL, Dyall SC, Curran OE, Priestley JV, and Michael-TItus AT. (2006). Omega-3 faty acids improve recovery, whereas omega-6 fatty acids worsen outcome, after spinal cord injury in the adult rat. J Neuroscience 26, 4672-4680.

Lewis MD, Bailes J, (2011) Neuroprotection for the warrior: dietary supplementation with omega-3 fatty acids. Mil Med 2011 Oct; 176(10):1120-7.

 

Mills JD, Bailes, JE, Sedney CL, Hutchins H, and Sears B. (2011). Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J. Neurosurgery 114, 77-84.

Mills JD, Hadley K, and Bailes JE. (2011). Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery 68, 474-481; discussion 481.

Tufts Center for the Study of Drug Development, Tufts University; http://csdd.tufts.edu/new/complete_story/pr_tufts_csdd_2014_cost_study, 2014

 

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.

 

 

 

Adrenal Tremor, Parkinson’s Disease and the Wheat Free Diet

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This is a Case Study of a 13 y/o boy who was raised on a wheat free diet (WFD) since age 4.  As an infant,  he  experienced monthly ear infections and was placed on prophylactic antibiotic therapy.  His pre-school years were mired with monthly strep throat infections. Occasionally, he had concurrent small red blotches, indicative of rheumatic fever, on his  torso.  A tonsillectomy was recommended by his pediatrician.

He began a WFD at age 4, the strep throat infections ceased …. unless he ingested wheat without antihistamine prophylaxis. Occasionally, he ate a piece of wheat pizza at school without a immediate anti-histamine.  Subsequent strep throat infections would ensue resulting in swollen cervical lymph nodes, a flushed face, swollen, red and pussy tonsils, but no fever.  All infections presented similarly, however not all tested positive for strep.   This condition was treated with antibiotics and resolved in a few days.  (Please see the www.wheatfreediseasefree.com post on “Keep the Tonsils, Pull the Strep Throat”).

As a pre-schooler,  the boy had wound healing difficulties.  During his middle school years, he experienced anxiety, fatigue, a lack of physical maturation, restless legs, painful joints, middle belly weight, athlete’s foot, and a slightly curved back.

At age 13, he ate two pieces of wheat pizza without antihistamine prophylaxis.  In the days following, his face flushed intensely, cervical lymph nodes swelled, but no fever was present.  His back was painful at the level of his adrenals. He experienced extreme fatigue, his eyes were sensitive to light, and he had a tremor.  The tremor traveled down his spine and caused his fingers to vibrate.  He was started on his standard Azithromycin antibiotic therapy. However, the condition did not resolve.

Within a couple days he “crashed“.  He had sufficient energy to be active for a couple of hours in the morning and then he lived on the couch for the remainder of the day.  He headed for bed shortly after dinner. Any form of stress intensified the tremor including homework or attending school.  He was started on a second antibiotic.

Differentials considered included infection, PANDAS, serotonin syndrome, and depression.  Medical personnel questioned whether he was avoiding school.  Blood panels were negative.  EEG was negative.  He was prescribed Zoloft to control the tremor.  This drug made him sick and was discontinued.

One month later, a naturopathic physician identified the boy’s flushed face as being caused by adrenal problems.  Through intracellular saliva testing, he was found to be adrenal insufficient.  The flashlight adrenal insufficiency test was positive.  To support his adrenals he began began a supplemental therapy of vitamin C (1000mg/day), B complex (200mg/day), adrenal cortical extract, minerals, vitamin A, CoQ10, vitamin E, spirulina, quercetin, a probiotic, 1g/day of omega-3 fish oil (DHA+EPA) and 1000mg/day of calcium citrate.  His energy levels gradually improved but the tremor continued.

Sugar, high fructose corn syrup, caffeinated drinks, and deep fried, greasy foods harmful to his adrenals were removed from his diet.  The high levels of fruit juice previously consumed were replaced with low, no sugar, or sugar substitute  juices.

It was determined that wheat contains methionine, lysine and threonine.  Methionine controls the hypophyseal-pituitary-adrenal (HPA) axis and is involved with cardiac rhythm.   Lysine is found in collagen thus supports wound heading and dental pulp formation. Threonine supports tooth enamel formation. Hypothesizing that the patient was deficient in these amino acids due to his WFD,  he was started on 1500mg/day of methionine and 1000mg/day of lysine. The boy craved red meat and eggs.  His diet was modified to include methionine containing foods such as brown rice, oranges, additional red meat, eggs, nuts, spinach, onions, peas, yogurt, and popcorn.  Within a week, the boy had regained sufficient energy to work on small hobbies.

Within a month, he began to experience some quick, sharp chest pain.  Methionine is stored in the heart.  The methionine dosage was reduced to 1,000mg/day.  Although he had more energy and felt better, the facial flushing, swollen lymph glands, fatigue, back adrenal pain, and tremor continued.

A urine amino acid profile showed the boy’s methionine level (with supplementation) in low normal range.  Also in low normal range were phosphoserine, taurine, phosphoethanolamine, aspartic acid, hydroxyproline, serine, asparagine, alanine, tryptophan, carnosine, and anserine.   Some success has been found with taurine in relieving tremor.  He was given a trial of 1000mg/day of taurine.  His energy levels increased, however evening doses made it difficult to sleep and there was no improvement in the tremor.

Repeat urine and blood amino acid profiles showed phosphoserine as the only amino acid below normal range.  The patient was supplemented with 1,000mg/day of serine.  One week post therapy, he developed a skin rash on his arms and legs.  Serine therapy was discontinued then reduced to 500mg/twice each week.  The tremor persisted.

Next, the physiological function of each of these amino acids was addressed in relation to the patient’s signs/symptoms.  Proline was found to be a critical component of cartilage and important to joint structure.  Proline works with vitamin C in this capacity and can be synthesized by glutamic acid.  Arginine was important in wound healing, the production and release of growth hormone, insulin, and glucagon release, collagen synthesis, and GABA production. Arginine can be produced from glutamic acid or proline.  Glycine was critical to GABA neurotransmitter and energy production. GABA was important to inhibitory nerve function. Tyrosine was important to the production of neurotransmitters dopamine, norepinephrine, epinephrine, and melanin.  This patient’s grandfather had Parkinson’s Disease which involves low neurotransmitter levels in the Tyrosine – Dopamine Pathway.

Hypothesizing that the boy’s current amino acid levels may not be sufficient for the age dependent physical growth, adrenal stress due to methionine deficiency, and adrenal stress due to the wheat hypersensitivity reaction, this patient was additionally supplemented with 1500mg/day glutamine,  1500mg/day glycine, and 1000 mg/day tyrosine.  After one week of therapy,  the tremor was alleviated and would resume only  under stressful conditions.

After several months, the individual dosages of amino acids were replaced with a 750mg amino acid complex capsule, three times each day. The patient continued to improve.  This complex differed from ingesting protein rich foods in that all 20 amino acids were given concurrently through the complex.  All 20 amino acids must be present concurrently for  protein synthesis to occur.  Supplementation of the 20 amino acid complex relieved the tremor whereas his protein rich diet did not.

The patient returned to school six months post amino acid therapy initiation with improved physical activity levels, reduced anxiety, and alleviation of restless legs.  The daily tremor was absent except under stressful conditions.  His night time activities were kept to a minimum to ensure sufficient rest.

In subsequent years, he remained on 1500 mg/day amino acid complex, 1 gram of DHA+EPA omega-3 fish oil, B complex 100mg/day, vitamin C 1000mg/day, bovine adrenal cortex 340 mg/day, calcium 1000mg/day,  lysine 500mg/day, choline 500mg/day, 5-HTP 100mg/day, probiotic, and minerals.  It appeared that minimal amounts of these supplements are required to maintain good health.

Six years post presentation, this patient continues with occasional stress and fatigue. This is typically visible as facial flushing on the outer periphery of his cheeks.  The tremor has been alleviated under normal and stress conditions.  This patient continues on a WFD and ingests no wheat.  He ingests minimal sugar and deep fried foods, and no caffeine.  Accidental wheat ingestion receives immediate antihistamine and aspirin prophylaxis. The patient is careful to obtain sufficient rest, take supplements, and eat healthy food.  His back continues to be hunched causing him back, neck, and knee pain, but is otherwise most healthy.

 

Copyright © 2013.  All rights reserved.

Photograph: 8 week old dobie pup

Disclaimer:  The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice.   Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist.  Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material.  We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.