Study Spots Potential Stroke Drugs
DURHAM, N.C. -- Using a novel screening technology, Duke University Medical Center researchers have shown that drugs called cardiac glycosides can protect brain cells from death after stroke in laboratory models, and that the drugs are effective even if delivered six hours or more after the onset of stroke conditions.
"This discovery is exciting because it may lead to interventions to prevent or lessen the amount of brain damage suffered after stroke," said Donald C. Lo, Ph.D., director of the Center for Drug Discovery and associate professor of neurobiology at Duke, and primary investigator on the study.
The findings will appear during the week of June 19, 2006, in the early online edition of the Proceedings of the National Academy of Sciences and in the July 5 printed issue of the journal. The study was funded by Cogent Neuroscience Inc., a Durham-based biotechnology company spun off from Duke to foster neurogenomic and chemical biological approaches to drug discovery for neurological diseases.
Stroke is the third leading cause of death in the United States, with more than 700,000 new cases diagnosed each year. Strokes occur when the blood supply to the brain is cut off either by a blood clot or the bursting of an artery. Patients who survive can experience brain damage that leads to loss of language and cognitive ability and permanent extremity weakness, among other problems.
Currently, only one drug has been approved by the Food and Drug Administration to treat stroke -- and it faces serious limitations, Lo said. Called recombinant tissue plasminogen activator, the drug must be given within a three-hour window after the onset of stroke. Also, because the drug is delivered intravenously and acts by breaking blood clots, it is ineffective against "hemorrhagic" strokes that happen when an artery bursts.
The cardiac glycosides that the Duke team tested against stroke are now commonly used for treating heart disease, but they had never previously been investigated for use in stroke therapy, Lo said. In heart disease, the drugs increase calcium levels in heart cells and thereby strengthen beating of the heart.
Lo speculates that cardiac glycosides may exert their beneficial effect during stroke in an analogous manner, by restoring calcium to healthy levels in brain cells and thereby preventing cell death. Calcium plays a key role in regulating normal cell function, and any changes in its cellular concentration -- such as those caused by stroke -- can be toxic.
In their study, the researchers screened a broad range of druglike compounds in brain slices taken from rats and induced to develop neurological conditions that mimic focal ischemia, the most common form of stroke. Of the thousands of compounds tested, the researchers found that the cardiac glycoside neriifolin had a particularly potent protective effect against ischemic damage -- the destruction of areas of the brain caused when blood supply stops -- and that the drug worked even when delivered six hours after the onset of stroke.
Because of the difficulty of recognizing symptoms, which can include slurred speech, weakness of extremities and visual changes, most patients don't seek treatment for stroke until many hours after the onset, rendering current drug therapy largely ineffective. "The process of cell death begins immediately upon onset of stroke, but the real damage can happen hours and even days later," Lo said. "So there is a great need for therapies that can be used for longer periods following stroke than today's treatments.
"This discovery is very promising," he said. "We are now looking forward to taking this research to the next step and testing neriifolin and other cardiac glycosides further in animal models and hopefully, someday, in humans."
Their experimental model also may have broader scientific value, the researchers said.
"We created a screening system in which we could deliver drug molecules against all known drug targets in the brain slices, rather than against just the few targets that have previously been implicated in brain cell protection," Lo said. "Since we had no preselected bias, we were able to evaluate the widest possible range of drug targets, and this is how we discovered the unexpected protective properties of cardiac glycoside drugs such as neriifolin."
Said study team member David S. Warner, M.D., a professor of anesthesiology at Duke, "This new screening system, which allows us to deliver a vast number of drugs to tissue and rapidly determine which might work and which won't, has very exciting implications for the effort to find effective stroke treatments."