Hidden in the stately steppes of gentle rice paddies, nestled in shiny clusters of red and purple palm fruit, lurking in tiny annatto seeds from the achiote tree… lies a quartet of potent anti-inflammatory, highly protective molecules called tocotrienols. They are cousins to the four tocopherols. Together, all eight comprise the Vitamin E family, a lipid-loving arsenal of molecules essential to health. Each has its own healing profile. According to molecular biochemist Chandan Sen, of Ohio State University, “Current studies of the biological functions of vitamin E continue to indicate that each member of the vitamin E family possesses unique biological functions often not shared by other family members.”
In 2008, we brought you the latest tocotrienol research, focusing then on the delta and gamma forms (FOCUS July 2008). Research has advanced at a quick pace since then, and we are devoting much of this issue to the newest findings on all of these remarkably potent molecules. Their biological impact turns out to effective in preventing and repairing stroke-related vascular damage, atherosclerosis, elevated cholesterol, and non-alcoholic fatty liver disease. Tocotrienols work not only as antioxidants, but through specialized mechanisms that directly regulate key inflammatory pathways in the body.
For a long time, tocotrienols were like the Cinderella of Vitamin E science—relegated to the corner and ignored. Vitamin E research focused almost exclusively around alpha-tocopherol—discovered in 1922, isolated and analysed in 1936, and dubbed the “fertility factor” because it is necessary for reproduction. We know that alpha-tocopherol has its own transport system (alpha-tocopherol transport protein, or TTP). This protein controls the distribution of alpha-tocopherol to cells and tissues throughout the body.
But in the last decade, a number of princes have kissed our Cinderella, and there is a growing body of impressive research on tocotrienols. In 2005, the definition of vitamin E in the Merck Manual had no reference to tocotrienol. Today, the manual recognizes that “Vitamin E is a group of compounds (including tocopherols and tocotrienols) that have similar biologic activities.” In addition, in 2010 the FDA bestowed GRAS status on all tocotrienols. Tocotrienols turn out to offer unique protection against complex metabolic conditions, including heart disease, atherosclerosis, stroke, fatty liver disease, and metabolic syndrome.
“Tocotrienols exhibit health benefits quite different from that of tocopherols, and in most cases, these activities are superior for human use,” states biochemist Bharat B. Aggarwal, PhD, of The University of Texas M.D. Anderson Cancer Center in Houston, where he and his team study curcumin, resveratrol, tocotrienols and other natural compounds that might help us to defeat cancer. “We now know different isomers of tocotrienols exhibit distinct activities. While alpha-tocotrienol is highly effective in the brain for cerebral ischemia, gamma and delta tocotrienol exhibit strong anti-cancer and anti-inflammatory activities.”,,,
Most importantly, says Aggarwal, tocotrienols work on multiple pathways: “In the last few decades, too much emphasis has been placed on designing drugs that hit a single target. I call it target practice—one gene, one target. However, most diseases area result of complex dysregulation of multiple genes and signaling pathways. Promising oral agents like tocotrienols are bioavailable, work on multiple pathways, and are already recognized as safe.”
In this issue we present:
• New studies suggesting that tocotrienols might protect the brain from stroke and repair stroke-induced damage.
• Groundbreaking research showing tocotrienols can improve and often cure fatty liver disease, improve end-stage liver disease, and protect hepatic function.
• Pathways by which tocotrienols protect neurons, prevent neuronal cell death, inhibit cholesterol and beneficially alter its fractions, and dampen inappropriate inflammation.
• Studies showing that tocotrienols reduce cholesterol, and improve atherosclerosis and arterial stiffness.
Let’s Start With Stroke: Neuroprotection and Tocotrienols
If one single scientist has advanced our understanding of the brain and tocotrienols, it is molecular biochemist Chandan Sen, PhD, tenured Professor of Surgery and the Executive Director of the Ohio State University Comprehensive Wound Center.(See Interview With Chandan Sen, PhD, From A Single Cell to the Human Brain). In Sen’s words, “On a concentration basis, the neuroprotective effects of nanomolar tocotrienol represent the most potent biological function of all natural forms of vitamin E.”2 Uniquely, they are biologically active in the body at concentrations far lower than that of the allied tocopherols.
Stroke-induced lesions in tocotrienol treated dogs were significantly reduced in volume. Loss of white-matter fiber tract connectivity—the connectivity between different regions within the same hemisphere of the brain—was also reduced.
Working under famed Vitamin E expert Lester Packer, PhD at The University of California at Berkeley, Sen spearheaded original research into all eight vitamin E isomers in the late 1990’s. One vitamin E fraction stood out. “We were astonished to find that alpha-tocotrienol was significantly more effective in preventing neurodegeneration in cells in vitro than any other molecule,” says Sen.1 It prevented neuronal death that might otherwise have occurred due to excess glutamate, the most abundant neurotransmitter in the brain. Later in vitro research found that neuronal cells could completely recover even several hours after a glutamate challenge, when treated with alpha-tocotrienol. Remarkably even if glutathione remained depleted, cell death was prevented.1
Further research by Sen and colleagues showed that alpha-tocotrienol protected hypertensive rodents from stroke damage. Stroke was induced in hypertensive rats, and their brains were removed to measure the size of the stroke-induced lesions. Rats supplemented with alpha-tocotrienol had significantly smaller lesions.10 Then a randomized, blinded trial was conducted in dogs. Dogs were given mixed palm tocotrienols for 10 weeks, or a placebo. Stroke was induced and the volume of brain lesions measured using high resolution MRI bothone and twenty-four hours after the stroke was induced., Stroke-induced lesions in the treated dogs were significantly reduced in volume. Loss of white-matter fiber tract connectivity—the connectivity between different regions within the same hemisphere of the brain—was also reduced. Circulation to the ischemic region of the large, middle cerebral artery was measured by cerebral angiogram, and was improved in the tocotrienol-supplemented dogs.11,12
The researchers concluded that tocotrienols improved circulation, inhibited inflammatory molecules, and was powerfully neuroprotective. “Tocotrienols are a natural neuroprotective agent,” says Sen. “The neuroprotective property of tocotrienols hold good not only in response to glutamate challenge but also in response to other insults such as homocysteic acid, glutathione deficiency and linoleic acid-induced oxidative stress.”1,2
Human Trials Are Next
Sen and colleagues are now setting the stage for human trials, called the Phase II Natural Tocotrienol Against Ischemic Stroke Event study. They have already concluded human trials proving that oral tocotrienols are both safe and well distributed in organs and the brain. They are currently researching optimal dosing regimens, before they design a study on tocotrienols in humans. Given the stream of positive data in every single study to date, it is likely we have in tocotrienols a potent and bioavailable, safe oral supplement to help prevent stroke and repair stroke damage.
If tocotrienols protect against stroke, they may well protect against other kinds of neurodegeneration, perhaps even the normal defects of aging. In a 2008 study, tocotrienols proved protective for a genetic neurodegenerative disorder called familial dysautonomia (FD), primarily affecting individuals of Ashkenazi Jewish descent. The mutations responsible for FD were found to occur in a gene encoding a protein (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complexassociated protein) termed IKAP. Over time neurons become progressively demyelinated. Autonomic “crises” include episodic vomiting, seizures,hypertensive crises, and many other symptoms. At the Laboratory for Familial Dysautonomia Research at Fordham University in New York, director Berish Y. Rubin and his colleagues screened hundreds of compounds and found that two—tocotrienols and epigallocatechin gallate (a component of green tea) were able to increase the amount of functional IKAP protein. After 3-4 months of tocotrienol supplementation, 80% of patients reported a significant decrease in the number of crises. “Individuals taking these compounds have seen a dramatic reduction in the symptoms associated with FD and have had a dramatic improvement in their quality of life,” states Rubin.,,,
Tocotrienols Can Cure Non Alcoholic Fatty Liver Disease
Thirty patients with non-alcoholic fatty liver disease were supplemented with mixed tocotrienols for a year, and 15 were completely cured. Another five showed significant improvement in the condition.
When orally supplemented, tocotrienols reach their maximum concentration in the liver compared to other organs. In fact, ground-breaking new research shows that tocotrienols can actually reverse non-alcoholic fatty liver disease, as well as improve deadly, end-stage liver disease.
Non-alcoholic fatty liver disease (NAFLD) is considered part of a spectrum of diseases called metabolic syndrome: they include obesity, diabetes, hypertension, high cholesterol, cardiovascular disease, and fatty liver. The incidence of NAFLD is surprisingly high—it afflicts 15-30% of Americans (studies in Europe, Japan and Malaysia report similar rates). Yet because it’s asymptomatic, and there is no blood biomarker for the condition, it’s often overlooked. The gold standard for NAFLD diagnosis currently remains ultrasound radiography.,,,,
Yet NAFLD is not benign. Twenty percent or so progress to the more severe non-alcoholic steatohepatitis (NASH), and from there, some patients will go on to cirrhosis, liver cancer, or liver failure. NAFLD patients also have a greater risk of atherosclerosis. According to pharmaceutical technologist Enrico Magosso, PhD, “The dangers of NAFLD are grossly underestimated due to two reasons: the lack of understanding of the pathogenesis; and the lack of an effective pharmacological treatment.”
In 2010, at the Liver Meeting of the American Association for the Study of Liver Diseases (ASSLD), Boston, Magosso and his colleagues reported a ground-breaking study that tocotrienols could improve, and even cure, NAFLD. Thirty patients were supplemented with full-spectrum palm tocotrienols for a year, and fifteen were completely cured. Another five showed significant improvement in the condition (at least one degree of amelioration of their fatty liver score, as evidence by ultrasound diagnosis).17,23
Tocotrienols Improve End Stage Liver Disease Scores
50% of end-stage liver disease participants awaiting transplant and receiving oral mixed tocotrienol supplementation had a reduction in their end stage liver disease (MELD) score…4 of 6 participants with hepatitis C and the sole participant with hepatitis B had a reduced score following treatment.
Tocotrienols may also improve a far more serious liver condition: end-stage liver disease (ESLD). Tocotrienols’ ability to impact deadly liver disease was a serendipitous surprise to Chandan Sen and his colleagues when they began a trial to prove that tocotrienols were efficiently absorbed into skin, fat, human organs and the brain. The researchers supplemented individuals on organ transplant lists (so that when their organs were removed, testing could be done) as well as severe epileptics who needed brain surgery, and in whom at least a gram of brain tissue would be removed. Supplementation time averaged a month.
Patients awaiting liver transplant are always given a MELD (model for end stage liver disease) score. The MELD scale ranges from 6 to 40, with the highest scores indicating poorest liver function and greatest need for a transplant. MELD score is a reliable marker for mortality, and does not improve over time. During the study, clinicians reported back that the MELD scores of tocotrienol supplemented patients were improving! Sen and colleagues amended the trial design to test the impact of tocotrienols on MELD scores. They report, “The effect… was most evident in patients with viral hepatic cirrhosis. In the current study, 50% of ESLD participants receiving oral tocotrienol supplementation had a reduction in their MELD score…4 of 6 participants with hepatitis C and the sole participant with hepatitis B had a reduced MELD score following treatment.”
Why are tocotrienols so effective in liver disease? Magosso speculates they impact multiple pathways. Animal studies show tocotrienols help prevent lipid peroxidation, and inhibit inflammatory mediators such as NFKappaB and TNFα, all of which are thought to be involved in NAFLD.17 They also work on peroxisome proliferators-activated receptors, otherwise known as PPARs. Several well known antidiabetic drugs are designed to reduce insulin resistance by working on PPARs.17,,
Tocotrienols Improve the Function of Arteries
Arterial compliance may sound like an odd phrase—are blood vessels rebellious or obedient? In fact, arterial compliance (or elasticity) is a key measurement of cardiovascular health. It refers to the action by which an artery yields to pressure or force without disruption. When arteries are stiff, their compliance decreases. Reduced arterial compliance is common in hypertension, and it can even appear in individuals with normal blood pressure, as an indicator of their potential for hypertension. Arterial stiffness is an important indicator of cardiovascular disease.
Tocotrienols increase arterial compliance. In 2008, a randomized, placebo-controlled study on 36 healthy males measured arterial compliance after two months of tocotrienol supplementation. Tocotrienols were supplied as bio-enhanced full-spectrum palm tocotrienols. The men received either a placebo, or tocotrienols (at 50, 100 or 200 mg daily). Carotid-femoral pulse wave velocity (PWV), a proven measure of arterial stiffness, was used. It measures the time it takes for the arterial pulse to move from the carotid to the femoral artery. Men taking either 100 mg or 200 mg of mixed tocotrienols daily showed significant improvement in arterial compliance.,
Bioavailable Tocotrienols Lower Cholesterol
Men taking either 100 mg or 200 mg of mixed tocotrienols daily showed significant improvement in arterial compliance (elasticity)-a key marker for cardiovascular risk.
Tocotrienols may also lower total cholesterol. They contain a side chain that increases a molecule in the cell called farnesol. That molecule signals the degradation of an enzyme responsible for the production of cholesterol (the enzyme is 3-hydroxy-3-methyl-glutaryl-CoA, or HMG-CoA). We discussed this at length in our 2008 newsletter. While statins, especially in high doses, are like a metaphorical sledgehammer inhibiting this enzyme, and blocking the pathway so that co-enzyme Q10 is also inhibited, tocotrienols are far gentler, with no apparent side effects.
A 2001 study from the University of Wisconsin compared tocotrienols, statins, or a combination of the two on cholesterol markers. Researchers put 28 individuals with high cholesterol on a restricted diet for a month, and then gave them either 50 mg of mixed tocotrienols, 10 mg of the statin drug Mevacor, or a combination of the two. In the 50 mg tocotrienol group total cholesterol was lowered by 14% and LDL by 18%. In the Mevacor group total cholesterol was lowered by 13% and LDL by 15%. In the combination group total cholesterol was lowered by 20% and LDL by 25%. The researchers then tested diet and tocotrienols alone—at doses of 25 mg, 50 mg, 100 mg, and 200 mg a day. 90 people were studied, and the 100 mg a day dose worked most efficiently, lowering total cholesterol by a very impressive 20% and LDL by a clinically highly significant 25%.
However, some studies on tocotrienols and cholesterol have shown equivocal results. According to researcher and pharmaceutical scientist Yuen Kah Hay, PhD, of the School of Pharmaceutical Sciences at the University of Science Malaysia, two studies showed that supplementation with 200 mg of mixed or pure tocotrienols in subjects restricted to a controlled diet led to a reduction of 8-16% of total cholesterol and LDL cholesterol within 4 weeks. Even without a controlled diet there were similar improvements. Yet other studies showed that supplementation with up to 240 mg of tocotrienols did not lower cholesterol. “The discrepancy might be due to differences in the composition of the supplements as well as differences in the bioavailability of dosage forms used,” writes Yuen. “For example, a high-tocopherol content (30% and above) in the tocotrienol supplement has been found to attenuate the cholesterol lowering activity of the mixture in chickens, as well as reducing the oral bioavailability of the tocotrienols…This might explain the absence of cholesterol lowering activity observed…Moreover, the bioavailability of lipid soluble drugs was reported to be greatly influenced by the type and volume of oil administered as well as the delivery systems used. A formulation that gives both consistent and enhanced absorption of the tocotrienols will be advantageous.”
Thirty-two individuals with high cholesterol were randomly assigned to either 300 mg of mixed tocotrienols, or placebo capsules, for six months. The serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group decreased significantly.
A 2011 study by Yuen and colleagues found that a self-emulsifying formula of tocotrienols effectively lowered cholesterol levels. Thirty-two individuals with high cholesterol were randomly assigned to either 300 mg of mixed tocotrienols, or placebo capsules, for six months. The researchers report that “the serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group were decreased significantly…after 4 months of supplementation and the reduction persisted till the end of the 6-month study… moreover, there was a very impressive 22-fold increase in the total tocotrienol concentrations from baseline during supplementation compared to the placebo group, while the concentration of tocopherol recorded onlya modest increase. On the other hand, the serum cholesterol, total tocotrienol and tocopherol concentrations of subjects in the placebo group remained essentially unchanged.”31
The Cellular Pathways to Potent Protection
By what molecular magic do tocotrienols protect the heart, brain and liver? Research is now elucidating many of the pathways. In the brain, there are at least four antioxidant-independent pathways by which tocotrienols might uniquely prevent neurodegeneration. They do so by regulating specific mediators of cell death.
Perhaps the most striking is the pathway regulated by the cSrc (short for “sarcoma”) gene. Scientists J. Michael Bishop and Harold E. Varmus were awarded the 1989 Nobel Prize in Physiology or Medicine for discovering this gene. Its pathway regulates normal and abnormal cell growth. Though this pathway has been studied intensively in cancer, it turns out that cSrc is also abundant in the brain. Overexpression in this pathway can lead to glutamate-induced cell death. Too much glutamate, the most abundant neurotransmitter in the brain, is potentially deadly to the brain’s glial cells, cortical neurons, and other types of neurons.7,9, “cSrc is involved in neurodegeneration in vivo,” states Sen. “Our pursuit for the neuroprotective mechanisms of tocotrienols led to the first evidence demonstrating that rapid cSrc activation plays a central role in executing neurodegeneration. Consistently, it was demonstrated in a subsequent report that cSrc deficiency or blockade of cSrc activity in mice provides cerebral protection following stroke.” Alpha-toctotrienol powerfully inhibits expression of this pathway.32
The second pathway is that of lipoxygenase, a fatty acid metabolizing enzyme, which regulates a compound known as 12-Lox. Says Sen, “Our work led to the identification of 12-Lox as a key tocotrienol-sensitive mediator of neurodegeneration. 12-Lox represents a critical checkpoint in glutamate-induced neurodegeneration.” Metabolites of 12-Lox are capable of causing cell death. Alpha-tocotrienol directly interacts with this enzyme.7
Other pathways include that of phospholipase, another enzyme related to lipid metabolism and cell membrane viability, and the fourth involves MRP1 (also known as multi-drug resistance protein-1). All protect against neurodegeneration.7
For cholesterol, tocotrienols suppress the activity of HMG-CoA reductase, the hepatic enzyme responsible for cholesterol synthesis. And, according to a 2011 genomics study on tocotrienols by Dipak Das and colleagues at the Cardiovascular Research Center at the University of Connecticut Health Center, tocotrienols regulate several key, cholesterol-related proteins. “The results of the present study demonstrate that the two isomers of tocotrienols, alpha and gamma, render the hypercholesterolemic hearts resistant to ischemic reperfusion injury by lowering several hypercholesterolemic proteins and upregulating TGF-beta.” (Transforming growth factor beta is a protein that controls proliferation and cellular differentiation, as well as providing inflammation control).
Finally, tocotrienols regulate NF-kappaB, a protein complex that controls the transcription of DNA regulating genes that are critical for inflammation and immunity. NF-kappaB is particularly relevant to both chronic inflammation and cancer. This may have relevance not only to any disease involving inflammation, but also to aging, according to scientists Mary Kaileh, PhD and Ranjan Sen, PhD, of the Laboratory of Cellular and Molecular Biology at National Institute on Aging, Baltimore, Maryland. “It is widely hypothesized that NF-kappaB dysregulation accompanies human aging,” they note. “It is possible that regulat ed consumption of tocotrienols may counter this form of chronic NF-kB dysregulation without seriously impacting acute NF-kB responses that are essential for immune responses and thereby improve the quality of life of the elderly.”
Tocotrienols are the Future of Vitamin E Research
Before soybean oil is refined to obtain alpha-tocopherol, gamma-tocopherol is plentiful in the raw material, but in concentrating alpha-tocopherol, gamma-tocopherol was largely discarded. Recent research shows the criti cal importance of balancing ingestion of alpha-tocopherol with gamma-tocopherol, and gamma-balanced tocopherol formulas are now favored.
Likewise, tocotrienols obtained from fresh palm oil provide a rich balance of alpha-, beta-, gamma-, and delta-tocotrienols, along with a modest amount of tocopherols. As this newsletter shows, alpha-tocopherol does not interfere with the absorption of tocotrienols, as long as alpha-tocopherol is not artificially concentrated at excessive levels. In this particular case, nature offers a balanced combination of various vitamin E fractions that can offer therapeutic potential without interfering with each other.
We know now that meaningful research on vitamin E must define the isomer or isomers being studied. Studies that only look at alpha-tocopherol should not be titled as having researched “vitamin E”. And it is time for tocotrienols to take their place in the forefront of vitamin E research. From the heart to the brain, from the liver to life itself, tocotrienols are proving to truly be the next generation Vitamin E.
 Personal interview with Chandan Sen, PhD, January 27, 2013.
 Sen CK, Khanna S, Sashwati R. Tocotrienol Neuroprotection: The Most Potent Biological Function of All Natural Forms of Vitamin E. Micronutrient & Brain Health. CRC Press, 2009.
 Prasad S, Sung B, Srivedi P, Gupta SC, Aggarwal BB. Tocotrienols, Inflammation and Cancer, How Are They Linked? Tocotrienols: Vitamin E Beyond Tocopherols, Second Edition. CRC Press 2012.
 Kannappan R, Ravindran J, Prasad S, et al. (2010a) Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors. Mol Cancer Ther. 2010 Aug;9(8):2196-207. doi: 10.1158/1535-7163.MCT-10-0277. PMID: 20682650 View Abstract
 Kannappan R, Yadav VR, Aggarwal BB. γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents. J Biol Chem. 2010 Oct 22;285(43):33520-8. doi: 10.1074/jbc.M110.158378. PMID: 20720018 View Abstract
 Personal Interview with Bharat B. Aggarwal, PhD, January 24, 2013
 Sen CK, Khanna S, Roy S, Packer L Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem. 2000. Apr 28;275(17):13049-55. PMID: 10777609 View Abstract
 Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK. Neuroprotective properties of the natural vitamin E alpha-tocotrienol Stroke. 2005 Oct;36(10):2258-64. PMID: 16166580 View Abstract
 Rink C, Christoforidis G, Abduljalil A, Kontzialis M, Bergdall V, Roy S, Khanna S, Slivka A, Knopp M, Sen CK. Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14100-5. doi: 10.1073/pnas.0806678105. PMID: 18779582 View Abstract
 Rink C, Christoforidis G, Khanna S, Peterson L, Patel Y, Khanna S, Abduljalil A, Irfanoglu O, Machiraju R, Bergdall VK, Sen CK. Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. J Cereb Blood Flow Metab. 2011 Nov;31(11):2218-30. doi: 10.1038/jcbfm.2011.85. PMID: 21673716 View Abstract
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 Email interviews with Enrico Magosso PhD, January 23-31, 2013
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