Tocotrienol - a potent neuroprotective agent

Two recent studies offer new evidence suggesting an alternative form of natural vitamin E can be taken by mouth and will reach the blood in humans at levels determined to protect against stroke and other diseases.

Vitamin E occurs naturally in eight different forms. The primary vitamin E on drugstore shelves is called tocopherol, or TCP. But another natural form of vitamin E surfacing as a potent neuroprotective agent in repeated Ohio State University Medical Center studies is tocotrienol, or TCT.

This form, while not abundant in the American diet, occurs naturally in palm oil; this vegetable oil is increasingly used in prepared foods because it has no trans fat.

In the first study of this form of the nutritional supplement in humans, Ohio State researchers determined that a moderate dose of tocotrienol reached concentrations in human blood plasma that would be more than adequate to protect against neurological damage that follows stroke. These findings were published in the May issue of the journal Antioxidants & Redox Signaling.

In a separate study, the scientists determined that TCT is effective at two concentrations, one at which it functions as an antioxidant, and another, lower concentration at which the supplement offers non-antioxidant protection. Both functions of TCT are directed against neurodegeneration. These findings were published June 26 in an online edition of the Journal of Neurochemistry.

"We have determined that when administered orally, tocotrienol can reach concentrations needed to serve these dual protective functions," said Chandan Sen, professor and vice chair of surgery, deputy director of the Davis Heart and Lung Research Institute at OSU, and senior author of both studies. "It is a regular dietary ingredient in Asia, so it can safely be a part of a daily diet within prepared foods or as a supplement in the United States . Can it be therapeutically used to prevent stroke? Results from animal studies are encouraging, but it is still too soon to tell for humans. More mechanistic and outcomes studies are warranted."

In the first study, collaborating scientists at Wayne State University fed participants 400 milligrams of a time-release formulation of a supplement containing primarily TCT. Researchers collected blood samples from the participants two, four, six and eight hours after supplementation.

Sen said the maximum TCT concentrations in the bloodstream of supplemented patients averaged concentrations between 12 and 30 times higher than that needed to completely prevent stroke-related neurodegeneration as determined by earlier research.

Conventional wisdom has suggested that TCT, if eaten, cannot be carried to organs because the protein known as tocopherol transfer protein (TTP), which delivers TCP throughout the body, doesn't transport TCT very well.

"Our results demonstrate that TCT is efficiently delivered to the bloodstream despite the fact that the transfer protein has a lower affinity for TCT than it has for TCP," Sen said. Absorption of TCT is increased when the supplement is taken with fat-containing food, so the research participants took the study supplement with a high-fat (60 grams) meal to increase the efficiency of absorption.

The findings corresponded closely with previous work as well as the more recent study that sought to determine the levels at which TCT functions as an antioxidant, an agent that protects cells against the effects of free radicals. Free radicals are potentially damaging by-products of energy metabolism that can damage cells and are implicated in the development of cardiovascular disease and cancer. The tocopherol, or most common, form of vitamin E is known for its antioxidant properties.

In previous studies, the scientists found that moderate oral doses of TCT before a stroke significantly reduced stroke injury in hypertensive rats.

In the more recent study published in the Journal of Neurochemistry, researchers observed the effects of TCT on neurological damage that can be caused in two different ways: through the presence of homocysteic acid, which in excess can cause vascular and neuronal lesions associated with cardiovascular disease, and the fatty acid linoleic acid, which can directly stimulate damaging free radical activity. Fatty acids are related to stroke: They rapidly accumulate when a clot in a vessel stops blood flow to the brain, and play a role in irreversible brain injury.

To observe the TCT's effectiveness, rodent neural cells were pretreated with extremely low concentrations of TCT; these cells avoided the cell death associated with toxicity caused by homocysteic acid. But to reduce free-radical activity and resulting neurotoxicity, the scientists found that a higher concentration of TCT was needed: Tocotrienol does not exhibit antioxidant properties until it reaches a concentration 10 to 25 times stronger than the concentration that prevented the cell death signal.