For release: Wednesday, June 14, 2006
A drug long used to treat diabetes significantly reduces brain swelling, neuron loss, and death after stroke in rats, researchers have found. The finding may lead to improved ways of treating stroke and other disorders in humans.
The drug, called glibenclamide or glyburide, appears to work by blocking channels, or pore-like structures, that open in cell membranes when the brain is deprived of oxygen. The opening of these channels allows sodium ions and water to flow into the cells, causing them to swell (a condition called edema). The flow of sodium into cells also triggers a flood of sodium and water into surrounding tissues, which increases intracranial pressure and damages cells. Current treatments for brain edema are only moderately effective, and the swelling is believed to be responsible for much of the brain damage and death that occurs in people who have severe strokes.
The study was led by J. Marc Simard, M.D., Ph.D., of the University of Maryland at Baltimore School of Medicine. It was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the April 2006 issue of Nature Medicine.*
Dr. Simard and his colleagues previously discovered a new type of ion channel, called an NCCa-ATP channel, in cells called astrocytes. These channels appeared to play a role in the cellular swelling that occurs after injury. Astrocytes normally act as support cells in the brain, but if the brain is damaged, they often swell and stop functioning correctly. They are then referred to as reactive astrocytes. Dr. Simard’s group found that the number of NCCa-ATP ion channels increased dramatically in reactive astrocytes from brain regions that had been deprived of oxygen (a condition called hypoxia) due to insufficient blood flow. The opening of these channels is controlled by a protein called sulfonylurea receptor 1 (SUR1). The researchers wondered if the same ion channels might play a role in ischemic strokes, which are caused by a block of normal blood flow in the brain.
In the new study, Dr. Simard and his colleagues found that levels of SUR1 increased significantly in the core of the infarct, or damaged brain area, by 2 to 3 hours after a severe middle cerebral artery stroke. The levels of SUR1 remained high for several hours, then declined as cells began to die — about 8 hours after the stroke. In the area surrounding the core of the infarct (called the peri-infarct region), levels of SUR1 increased later but stayed elevated for much longer.
The investigators then gave continuous infusions of glibenclamide, which blocks SUR1, under the skin of rats that had experienced either severe middle cerebral artery occlusion (MCAO) strokes or less severe thromboembolic strokes. Similar groups of rats were treated with a saline solution for comparison. The researchers measured the amount of edema in the rats’ brains as well as the extent of the brain damage after the strokes.
The overall effect of the glibenclamide was positive. Only 24 percent of rats given the glibenclamide treatment after severe MCAO strokes died, compared to 65 percent of rats that did not receive the treatment. The glibenclamide-treated rats had much less cerebral edema 8 hours after stroke. Brain-damaged regions were much smaller in rats treated with glibenclamide than in those treated with saline after thromboembolic strokes.
The researchers found evidence that post-stroke changes in tiny blood vessels (capillaries) led to a breakdown of the blood-brain barrier. This, along with an increase in SUR1 and in the acidity of areas surrounding the original brain lesion, allowed glibenclamide to selectively target the damaged areas of the brain.
"An interesting observation in this study is that the NCCa-ATP channel, which was originally found in astrocytes, is also found in endothelial cells and neurons," says Tom Jacobs, Ph.D., NINDS program director for stroke and cerebrovascular biology. "Treatment that targets this channel on different cell types affected by stroke offers a promising new way to treat edema."
While a number of treatments have been devised to try to limit brain damage after stroke, many of them have side effects that have prevented widespread use. In contrast, glibenclamide has been used safely to treat type 2 diabetes for decades, and it has few side effects other than an increased risk of low blood sugar (hypoglycemia), Dr. Simard says. However, the drug is currently available only in pill form, and people who have had a stroke or other trauma are often unable to swallow pills. Also, a continuous infusion would be needed in order to block the NCCa-ATP channels while their numbers increase in damaged regions after a stroke. A version of glibenclamide that can be administered intravenously is now being developed. This type of delivery will allow researchers to test the drug in humans following strokes or other types of trauma.
The researchers are now looking retrospectively at records of people who have had strokes while they were taking a drug similar to glibenclamide in order to determine if they developed less brain damage than people who did not take then drug. They also are investigating whether glibenclamide can prevent the weakening of capillaries that makes it dangerous to give the drug t-PA (tissue plasminogen activator) to stroke patients beyond the first 3 hours following a stroke, and whether the drug can prevent hemorrhage after spinal cord injury.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, Wed GA, Gerzanich V. “Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke.” Nature Medicine, April 2006, Vol. 12, No. 3, pp. 433-440.
-By Natalie Frazin
Last Modified January 31, 2007