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Tuesday, December 13, 2011

vitamin E-'Gifted' natural vitamin E tocotrienol protects brain against stroke in 3 ways

'Gifted' natural vitamin E tocotrienol protects brain against stroke
in 3 ways
Public release date: 5-Jul-2011
Contact: Chandan Sen


Ohio State University
'Gifted' natural vitamin E tocotrienol protects brain against stroke
in 3 ways
Columbus, Ohio - A natural form of vitamin E called alpha-tocotrienol
can trigger production of a protein in the brain that clears toxins

from nerve cells, preventing those cells from dying after a stroke,

new research shows.
This process is one of three mechanisms identified so far that this
form of vitamin E uses to protect brain cells after a stroke, meaning

that this natural substance might be more potent than drugs targeting

single mechanisms for preventing stroke damage, according to Ohio

State University scientists who have studied the nutrient for more

than a decade.
These researchers previously reported that the tocotrienol form of
vitamin E protects the brain after a stroke by blocking an enzyme

from releasing toxic fatty acids and inhibiting activity of a gene

that can lead to neuron death.
Vitamin E occurs naturally in eight different forms, and all of this
work is focused on the tocotrienol form, also known as TCT. The

commonly known form of vitamin E belongs to a variety called

tocopherols. TCT is not abundant in the American diet but is

available as a nutritional supplement. It is a common component of a

typical Southeast Asian diet.
In this new study, the researchers first clarified the role of a
protein called MRP1, or multidrug resistance-associated protein 1.

This protein clears away a compound that can cause toxicity and cell

death when it builds up in neurons as a result of the trauma of

blocked blood flow associated with a stroke.
They then determined that TCT taken orally influences production of
this protein by elevating the activity of genes that make MRP1. This

appears to occur at the microRNA level; a microRNA is a small segment

of RNA that influences a gene's protein-building function.
This is one of the first studies to provide evidence that a safe
nutrient -- a vitamin -- can alter microRNA biology to produce a

favorable disease outcome," said Chandan Sen, professor and vice

chair for research in Ohio State's Department of Surgery and senior

author of the study. "Here, a natural nutritional product is

simultaneously acting on multiple targets to help prevent stroke-

induced brain damage. That is a gifted molecule."
The research appears online and is scheduled for later print
publication in the journal Stroke.
Over the past decade, Sen has led numerous studies on how the TCT
form of vitamin E protects the brain against stroke damage in animal

and cell models, and intends to eventually pursue tests of its

potential to both prevent and treat strokes in humans. Approximately

795,000 Americans suffer new or recurrent strokes each year, and

stroke is the third-leading cause of death in the United States,

according to the American Stroke Association.
These latest research findings in mice follow a recent Food and Drug
Administration certification of TCT as "Generally Recognized as

Safe." The scientists conclude in the paper that even before clinical

trials can take place, "TCT may be considered as a preventive

nutritional countermeasure for people at high risk for stroke."
To determine the role of MRP1 in protecting brain cells, the
researchers compared the effects of an induced stroke in two groups

of mice: normal mice and animals that were genetically modified to be

deficient in the MRP1 protein.
Both groups of mice showed comparably decreased blood flow in the
area of the stroke, but the mice deficient in MRP1 had a larger

volume of tissue death than did normal mice.
The mice with the protein deficiency also had a 1.6-fold higher level
of a toxin that is cleared by MRP1. This toxin is called GSSG, or

glutathione disulfide, and these researchers have previously shown

that a failure to clear this toxin appears to trigger neuron death in

the brain after stroke.
"The protein has the effect of dredging out the toxin," said Sen, who
is also a deputy director of Ohio State's Davis Heart and Lung

Research Institute. "A significant finding in this work is the

recognition that MRP1 is a protective factor against stroke. Thanks

to tocotrienol, we were able to identify that path."
The presence of GSSG is linked to an excessive amount of glutamate
that is released in the brain after a stroke. Glutamate is a

neurotransmitter that, in tiny amounts, has important roles in

learning and memory. Too much of it triggers a sequence of reactions

that lead to the death of brain cells -- the most damaging effects of

a stroke.
This experiment showed for the first time that the loss of MRP1
function impairs the clearance of GSSG, and that MRP1 cells were

recruited to the site of the stroke in normal mice, indicating this

protein has a protective role in the brain after a stroke.
The researchers searched databases containing genomic data for a
microRNA that appeared to have potential to influence production of

MRP1. MicroRNAs bind to messenger RNA, which contains the actual set

of instructions for building proteins. When that connection is made,

however, the microRNA inhibits the building of protein from messenger

RNA. So an inverse relationship exists between a microRNA and a

protein it controls.
The researchers saw this very relationship in the cell study in which
they manipulated the candidate microRNA levels and observed the

effects of changing those levels on the presence of the MRP1 protein.
Finally, the researchers compared mice that were treated with TCT
supplements or corn oil as a control for 13 weeks before a stroke was

induced. The amount of damaged brain tissue was smaller in the mice

that received TCT supplementation than in the mice receiving corn

oil. In addition, TCT supplementation was associated with a lower

level of the candidate microRNA in the damaged brain tissue, as well

as an increase in the abundance of MRP1 cells at the stroke site.
"Essentially what we are showing with mechanistic explanation is that
tocotrienol protects neural cells. It is anti-neurodegenerative," Sen

said. "This form of vitamin E helped us identify three major

checkpoints in stroke-related neurodegeneration that were not known

before we began testing tocotrienols against neurodegeneration"
This research was supported by the National Institutes of Health.
Co-authors include Han-A Park, Natalia Kubicki, Surya Gnyawali, Yuk
Cheung Chan, Sashwati Roy and Savita Khanna, all of the Department of

Surgery and Davis Heart and Lung Research Institute at Ohio State.

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