Tocotrienols, the lesser-known but extremely important components of naturally occurring Vitamin E, can prevent neural damage following ischemic stroke, potentially improving post-stroke outcomes, according to a recent study by Dr. Chandan Sen and colleagues at the Ohio State University Department of Surgery.

But many people, even those who diligently take vitamins, could be missing out on this benefit because the majority of commercial supplements—including most popular multivitamin brands—contain only d-alpha-tocopherol, which is just one of the eight naturally-occurring forms of Vitamin E. The alpha-tocopherol form is ubiquitous because it is much less expensive to produce. But taking d-alpha-tocopherol in isolation may not be particularly healthy.

“Our research suggests that the different forms of natural vitamin E have distinct functions. The relatively poorly studied tocotrienol form of natural vitamin E targets specific pathways to protect against neural cell death and rescues the brain after stroke injury,” reported Dr. Sen, senior author of the current study.   “Here, we identify a novel target for tocotrienols that explains how neural cells are protected.”

Dr. Sen’s lab discovered the tocotrienols’ ability to protect the brain 10 years ago. The current study offers the most specific details yet uncovered about the mechanism underlying the neuroprotective effect, said Dr. Sen, who is also a deputy director of Ohio State’s Heart and Lung Research Institute.

Quelling Arachidonic Acid

Following the trauma of blocked blood flow associated with a stroke, an excessive amount of glutamate is released in the brain. Glutamate is a neurotransmitter that, in small amounts, has important roles in learning and memory. Too much of it triggers a sequence of reactions that lead to the death of neurons – the most damaging effects of a stroke.

The glutamate surge activates an enzyme called cytosolic calcium-dependent phospholipase A2 (cPLA2), which catalyzes the production of massive amounts of highly inflammatory arachidonic acid. This arachidonic acid flood is a primary factor in post-stroke neural damage.

Dr. Sen and colleagues used cells from the hippocampus region of developing mouse brains for their study. They flooded the cells with excess glutamate to mimic post-stroke conditions. Then, they introduced tocotrienols. The presence of the tocotrienols decreased the release of arachidonic acid by 60% when compared to cells exposed to glutamate alone. The neurons exposed to tocotrienols following the glutamate flooding were four times more likely to survive than those exposed to unchecked glutamate (Khanna S, et al.  Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A(2) and causes neuroprotection.  J Neurochem. 2010; 112(5): 1249-60).

A Novel Neuroprotective Mechanism

Dr. Sen’s group found that tocotrienols inhibit the cPLA2 enzyme, thus blocking arachidonic acid release. “We have studied an enzyme that is present all the time, but one that is activated after a stroke in a way that causes neurodegeneration. We found that it can be put in check by very low levels of tocotrienol,” he said. “So what we have here is a naturally derived nutrient, rather than a drug, that provides this beneficial impact.”

The amount of tocotrienols needed to achieve these effects is quite small – just 250 nanomolar concentrations, about 10 times lower than the average amount of tocotrienol circulating in humans who consume the vitamin regularly.

These findings build on a 2005 study published by Dr. Sen’s group showing that oral tocotrienol supplementation could protect against stroke, at least in rodent models. Tocotrienols effectively modulated two key molecular check-points: the c-Src and 12-lipoxygenase pathways, favoring survival of the neurons.  Tocotrienols lowered the tyrosine phosphorylation of 12-lipoxygenase, thus protecting the neurons from apoptosis (Khanna S, et al.  Neuroprotective properties of the natural vitamin E alpha-tocotrienol.  Stroke. 2005 Oct;36(10):2258-64).

Clearing Carotid Atherosclerosis

In humans, stroke often occurs when atherosclerotic deposits travel upstream and cut off the blood supply to part of the brain. There is some evidence that tocotrienols may prevent this, by clearing atherosclerotic blockage (stenosis) in the carotid arteries

Fifty patients with carotid stenosis were randomly assigned to receive either 160 mg daily of palm tocotrienols (gamma and alpha forms) with 64 mg of alpha-tocopherol in palm oil, or palm oil only as a placebo. After 6 months, the dosage in the treatment group was increased to 240 mg of tocotrienols with 96 mg of alpha-tocopherol.

At the end of the study, ultrasound scans of the carotid artery demonstrated that in the tocotrienol group, atherosclerosis was reduced and blood flow to the brain improved in 7 of 25 patients, while the condition had worsened in only two patients.  None of the patients in the control group showed improvements while ten showed a worsening of their condition (increased stenosis). No adverse effects were observed in either group (Tomeo AC, et al. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids. 1995 ;30(12):1179-83)

Scientists have known for years that there are 8 isomers (forms) of vitamin E:   the alpha-, beta-, gamma-, and delta-tocopherols,  and alpha-, beta-, gamma-, and delta-tocotrienols.  Most vitamin E and multivitamin supplements contain only the alpha-tocopherol isomer, the form taken by an estimated 99% of the population, based on a major vitamin E study (Slatore CG, et al. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer.  Am J Respir Crit Care Med. 2008 Mar 1;177(5):524-30.).

The problem is that when taken in isolation and in large doses, the alpha-tocopherol form tends to displace the other forms that may be available in food.  In 2003, Drs. Han-Yao Huang and Lawrence J Appel at Johns Hopkins University, showed that supplementation with alpha-tocopherol alone reduced plasma levels of gamma-tocopherol by 58% and delta-tocopherol from 50% to 13% in 184 human subjects (Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003 Oct;133(10):3137-40).

Given what the Ohio State group has shown about the neuroprotective effects of the tocotrienols—the very isomers that are displaced by alpha-tocopherol —it is possible that people taking common consumer brand multivitamins or vitamin E products might be increasing the risk of stroke and poor post-stroke outcomes. This is one of many reasons to steer patients toward higher-quality, more complete formulations obtained through practitioner level nutraceutical brands.

Sources of Natural Vitamin E

Natural food sources such as oats, barley, rye, wheat germ, rice bran oil and palm oil provide all 8 isomers of vitamin E, which the body intrinsically knows how to assimilate.  Unfortunately, many Americans simply do not eat these foods. And even those who do may not be getting as much as they need.

Owing to modern high-yield farming techniques, many crops have diminished nutrient density. Growers enhance the soil to make crops grow faster and look better, but this does not enhance the nutritional value of food. The truth is, one would need to eat huge amounts of tocotrienol-containing grains to receive optimal tocotrienol and tocopherol levels from food alone.

For many people, vitamin E supplementation makes good clinical sense, but it is important that patients understand the need for high-quality products that provide the full complement of beneficial tocotrienols and tocopherols. These products may cost more, but they are far more likely to deliver the benefits of vitamin E without the potential adverse effects of overloading on any one specific isomer.