Glutamate-induced changes in cPLA2 may be a novel mechanism of neuroprotection that was observed in response to nanomolar concentrations of a natural form of vitamin E.
Blocking the function of an enzyme in the brain with a specific kind of vitamin E may prevent nerve cells from dying after a stroke, new research suggests.
In a study using mouse brain cells, Chandan Sen, PhD, and colleagues found that the tocotrienol form of vitamin E—an alternative to the drugstore supplement—stopped the enzyme from releasing fatty acids that eventually kill neurons. The researchers have been studying how this form of vitamin E protects the brain in animal and cell models for a decade, and they intend to pursue tests of its potential to both prevent and treat strokes in humans.
“Our research suggests that the different forms of natural vitamin E have distinct functions,” said Dr. Sen, Professor and Vice Chair for Research, Department of Surgery, Ohio State University in Columbus. “The relatively poorly studied tocotrienol form of natural vitamin E targets specific pathways to protect against neural cell death and rescues the brain from stroke injury. Here, we identify a novel target for tocotrienol that explains how neural cells are protected.” The findings were published in the March issue of the Journal of Neurochemistry.
Vitamin E and Stroke
Vitamin E occurs naturally in eight different forms—the best-known of which is tocopherols. The form of vitamin E in this study, tocotrienol, or 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.
Dr. Sen and colleagues first observed tocotrienol vitamin E’s ability to protect the brain 10 years ago. The current study offers the most specific details about how that protection works, according to Dr. Sen, who is also the Director of Ohio State University’s Comprehensive Wound Center.
“We have studied an enzyme—cystolic calcium-dependent phospholipase A2, or cPLA2—that is present all the time, but one that is activated after a stroke in a way that causes neurodegeneration,” said Dr. Sen. “We found that it can be put in check by very low levels of tocotrienol. So what we have here is a naturally derived nutrient, rather than a drug, that provides this beneficial impact.”
Dr. Sen’s group had linked TCT’s effects to various substances that are activated in the brain after a stroke before they concluded that this enzyme could serve as an important therapeutic target.
Glutamate’s Role in Neuroprotection
Following the trauma of blocked blood flow associated with a stroke, an excessive amount of glutamate is released in the brain, noted Dr. Sen. Too much glutamate can trigger a sequence of reactions that lead to the death of neurons, the most damaging effects of a stroke.
The researchers used cells from the hippocampus region of developing mouse brains for the study. They introduced excess glutamate to the cells to mimic the brain’s environment after a stroke.
With that extra glutamate present, the cPLA2 enzyme releases a fatty acid called arachidonic acid into the brain. Under normal conditions, this fatty acid is housed within lipids that help maintain cell membrane stability.
But when it is free roaming, arachidonic acid undergoes an enzymatic chemical reaction that makes it toxic—the final step before brain cells are poisoned in this environment and start to die. Activation of the cPLA2 enzyme is required to release the damaging fatty acid in response to insult caused by high levels of glutamate.
Dr. Sen and colleagues introduced the tocotrienol vitamin E to the cells that had already been exposed to excess glutamate. The presence of the vitamin decreased the release of fatty acids by 60% when compared with cells exposed to glutamate alone.
Brain Cells and Tocotrienol
Brain cells exposed to excess glutamate followed by tocotrienol fared much better as well, compared with those exposed to only the damaging levels of glutamate. Cells treated with TCT were almost four times more likely to survive than were cells exposed to glutamate alone.
Though cPLA2 exists naturally in the body, blocking excessive function of this enzyme is not harmful, Dr. Sen explained.
Researchers have already determined that mice genetically altered so they cannot activate the enzyme achieve their normal life expectancy and have better outcomes following stroke.
The amount of tocotrienol needed to achieve these effects is 250 nanomolar, a concentration about 10 times lower than the average amount of tocotrienol circulating in humans who consume the vitamin regularly, noted Dr. Sen. “So you don’t have to gobble up a lot of the nutrient to see these effects,” he said.