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How brain cells die after a stroke and whether estrogen or estrogen-like drugs can save them is the focus of a new grant at the Medical College of Georgia.
"What we are studying is if estrogen or these estrogen-like drugs were there, would that have reduced stroke damage?" says Dr. Darrell Brann, MCG neuroscientist and principal investigator on a $1.7 million, five-year grant from the National Institute of Neurological Disorders and Stroke.
Preliminary data suggest that these substances not only help traumatized cells survive, they further enable post-stroke recovery by encouraging stem cells found in certain parts of the brain to mature into new brain cells.
The studies are in an area surrounding the core of the stroke called the penumbra, where cells might live or die in the hours and weeks following a stroke. "It's a very complex issue because what you have in a stroke is an area that is deprived of blood flow; this is usually called the ischemic core. Blood is not reaching it at all," says Dr. Brann, associate director of MCG's Institute of Neuroscience. "A lot of cell death goes on there because the cells have no nutrients coming in whatsoever. The penumbra, on the other hand, has some blood flow but it is quite diminished." And, it's a mixed blessing.
While the diminished oxygen levels enable some cells to eke by, they also enable production of free radicals, leftovers of normal metabolic processes that cause cell malfunction and death.
But oxygen alone is not to blame. Dr. Brann believes that kinases, enzymes that regulate the activity of proteins by putting phosphates on them, have an important role in the signaling cascade that causes the fragile cells to live or die. "This is a basic mechanism that is in all of us for regulation of cell signaling and to turn off different types of function. We know this process also is involved in cell death related to stroke." Dr. Brann wants to know how it's involved.
"We think free radicals are either turning on some of these kinases or these kinases are inducing the production of free radicals," he says. "There is a link between them and we are trying to figure out that link. Our hypothesis is that free radicals are inducing several of the key death kinases."
In a stroke animal model, he's analyzing the activity of known pro-death and pro-life kinases in the brain in the hours after stroke as well as the usual levels in a healthy brain. And, he's looking at whether estrogen and/or estrogen-like compounds can regulate pro-death and pro-life kinases in a beneficial way after injury.
"We are studying the kinases that are turned off, trying to characterize what are the pro-death and pro-life kinases turned on in stroke and the effect of estrogen, tamoxifen and raloxifene upon these kinases."
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He notes his studies are looking at whether these substances protect neurons after stroke, not whether they reduce stroke risk. The Women's Health Initiative, a 15-year study of more than 161,000 women by the National Institute of Health's National Heart, Lung and Blood Institute, showed that hormone replacement therapy, touted for its ability to reduce the risk of heart attack and stroke in postmenopausal women, appears to increase the risk of those conditions. While Dr. Brann and others still question some aspects of the study, possible ill effects of estrogen led him to include in his studies the estrogen-like drugs called SERMs, which act like estrogen in some tissues and as an anti-estrogen in others. These include tamoxifen, used to treat breast cancer and to reduce breast cancer risk in high-risk women by blocking the estrogen receptors found on most breast cancer cells, and raloxifene, which works like estrogen to keep bones strong but works as an estrogen agonist to protect the breasts.
Despite the interest in these compounds, their function in the brain has not been well studied. By understanding the steps to cell death and how these types of drugs alter the steps, "…you could design a SERM that could act on a particular tissue and have the desired effect," says Dr. Brann.
The potential of these substances to thwart the pro-death cycle seems a natural fit because estrogen and some of its metabolites have been shown in many systems to be a free-radical scavenger. Dr. Brann's preliminary studies support this, showing dramatically reduced levels of toxic superoxide, the major free radical, in stroke models treated with estrogen and tamoxifen before stroke. "We know they can do good things in other parts of the body, so what can they do to the brain?"
One additional good thing these substances may do is encourage stem cells found in the brain to rally to the stroke scene. "The old thought was that the number of neurons you have after development is all that you will ever have. The new thought is that is not exactly true," says Dr. Brann.
In fact, research has shown at least two areas of the brain have a nearby supply of stem cells that can develop into neurons and other types of brain cells.
Again, his preliminary work has shown that estrogen enhances this natural replacement process. "We can say the estrogen-treated group has more proliferation, neurogenesis is the word we use, going on in the subventricular zone of the brain four days after stroke."
Low and higher estrogen doses seem to work equally well; the jury is still out on whether tamoxifen and raloxifen can do the same. Dr. Brann is still looking at their impact and looking further at estrogen, too.
"Now what we have to do is look at two weeks, three weeks, six months. What happens? Do these new cells migrate out? Do they reach the area of infarct? We have to trace them. We have to track them. That is what the grant is about."