Estrogen shows potential as stroke treatment, UF animal studies show

A high dose of estrogen administered soon after a stroke can prevent a substantial amount of brain damage in laboratory animals, University of Florida researchers reported today (3/3/00) in the American Heart Association journal Stroke. When rats are injected with the female hormone within 30 minutes of a surgically induced stroke, the death rate for brain cells drops by 60 percent. Even three hours later, estrogen still can save 30 to 40 percent of the cells, said James W. Simpkins, chairman of the department of pharmaceutics in UF’s College of Pharmacy and director of the university’s Center for the Neurobiology of Aging. The study builds on statistical observations that postmenopausal women who take estrogen replacement therapy are more likely to survive stroke than those who do not. Simpkins, who has been studying estrogen for 25 years, noted that in previous laboratory studies, he and his colleagues have shown that giving the hormone before a stroke can protect against its harmful effects. “Here we have confirmation that it has potential for treating a patient who comes into the emergency room with stroke symptoms,” said Simpkins, who also is affiliated with UF’s Brain Institute and collaborated on the research with UF neurosurgeons Shao-Hua Yang and Arthur Day. Simpkins cautioned, however, that much more research needs to be done before anyone afflicted with stroke is treated with estrogen. Clinical trials will have to be conducted to test the safety and effectiveness of such an approach in humans, he said. An estimated 500,000 Americans suffer stroke each year, according to the National Institutes of Health, with approximately 80 percent of the attacks resulting from a clot that blocks the flow of blood to an area of the brain. Without oxygen and essential nutrients, brain cells begin to die. The more severe the die-off, the more pronounced the resulting physical and cognitive limitations, such as paralysis or difficulty speaking. In the UF study, researchers induced a stroke in female rats by surgically blocking the middle cerebral artery, the one most commonly implicated in human stroke. All the rats had previously undergone surgery to have their ovaries removed, so that no estrogen would be naturally circulating in their systems. “Our strategy was to load them up with as much estrogen as we could and to get the compound to the brain as quickly as possible with an intravenous administration,” Simpkins said. “We gave them about 20 times the amount that would normally have been in their bodies.” The rats were divided into several groups so that researchers could test the effect of estrogen administered at 30 minutes, and one, two, three or four hours past the inducement of the stroke. A control group received no therapy. “As time passed, the amount of tissue that was protected declined, which indicates that there is a window of opportunity to protect brain tissue. The earlier you are in that window, the better the outcome,” Simpkins said. “If you were past four hours, you wouldn’t expect to see any protection.” Current treatment for stroke generally consists of “clot-busting” medications, which can help dissolve the blockage if given soon after the onset of the brain attack. In contrast, estrogen potentially could preserve the brain cells for a time while blood flow is still inhibited. “There is the possibility that this would give physicians more time to open up the blood vessels with medications,” Simpkins said. In recent years, estrogen has claimed the research spotlight in connection with a variety of neurological problems, including Alzheimer’s and Parkinson’s diseases, as animal studies by Simpkins and others have demonstrated its ability to keep brain cells alive and healthy. Clinical trials are under way to determine its effectiveness in preventing or delaying the onset of Alzheimer’s in people. Meanwhile, Simpkins has been working to eliminate one drawback to estrogen as a universal therapy—its link to the development of female characteristics. Simpkins has devised estrogen compounds that appear to maintain the hormone’s protective capabilities without any feminizing effects. The UF study was supported by grants from the National Institute on Aging, the U.S. Army and Apollo BioPharmaceutics Inc. of Cambridge, Mass., which has licensed the rights to any commercial applications of this research.