For release: Wednesday, March 8, 2006
Stroke is the third leading cause of death in adults in the United States. Currently, the only approved drug treatment for acute stroke must be given within 3 hours from stroke onset. A recent study shows that a naturally occurring growth factor, called neuregulin-1, can protect nerve cells and decrease inflammation in an animal model of stroke when administered as long as 13 hours after the brain attack. This is the first study to show that neuregulin-1 can have a positive effect on the outcome after stroke in animals and could lead to new drug treatments for people.
“Even though you have cells dying immediately when there is a stroke, the cells continue to die for a time after the initial event. This is one of the reasons why it is so important to go immediately to the hospital once any sign of stroke is detected,” says Byron Ford, Ph.D., of the Morehouse School of Medicine Neuroscience Institute in Atlanta. “The ability of neuregulin-1 to protect and prevent further neuronal damage could result in a better recovery.” The study is published in the August 31, 2005 advance online publication of the Journal of Cerebral Blood Flow & Metabolism* and was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).
There are two main types of stroke: hemorrhagic stroke, where a blood vessel ruptures, causing blood to leak into the brain and ischemic stroke. With ischemic stroke, which accounts for 80 percent of the cases, a blood vessel that supplies blood to the brain gets clogged. Currently tPA (tissue Plasminogen Activator) is the only FDA approved treatment for stroke and is recommended for ischemic stroke treatment within 3 hours of the onset of symptoms. After 3 hours, the potential risk of hemorrhage or excessive bleeding outweighs the benefits of the drug treatment. Dr. Ford hypothesizes that the use of neuregulin-1 may offer an extended window of opportunity for therapeutic intervention after stroke.
In the Morehouse School of Medicine study, researchers blocked the middle cerebral artery in rats to interrupt the blood supply to the brain. Similar to stroke in humans, this deprivation of blood supply and oxygen caused brain cells to die within minutes and led to inflammation of tissue surrounding the site where the blood flow was obstructed. The scientists then examined the effects of administering neuregulin-1 to rats at different time intervals after the surgically induced stroke. Dr. Ford and his colleagues discovered that immediate administration of neuregulin-1 reduced cell death by 90 percent in the rats that were treated compared with rats that did not receive the compound. It also helped to prevent nerve cell loss after longer intervals.
“Neuregulin-1 protected neurons from damage even when administered as long as 13 ½ hours after the stroke's onset. At that point it protected 60 percent of the neurons,” says Dr. Ford. “Even two weeks after a single injection of neuregulin-1 we still saw no increase in the damage. The increased time period that neuregulin-1 is able to protect neurons after stroke would be a great benefit to stroke patients.”
Neuregulin-1 acts by blocking delayed neuronal death and decreasing inflammatory responses. Normally, the brain doesn’t make many receptors for neuregulin-1. However, after injury and inflammation, the number of receptors tends to increase. The scientists believe that this action helps to bind neuregulin-1 to the affected areas and helps to prevent further neuronal damage. The drug administration also translated to an improved clinical outcome in the model. The neuregulin-1 treated rats demonstrated significantly fewer neurological deficits when compared to animals that were untreated.
Previously, Dr. Ford had examined the protective effects of neuregulin-1 in vitro (in cells) and when administered before an induced stroke. However, this is the first study to demonstrate that the drug is an effective treatment when used after a stroke. The use of neuregulin-1 could have clinical benefits as both a pre- and post-stroke treatment.
“Neuregulin-1 has the potential to be successful where others have not,” says Dr. Ford. “Neuregulin-1 has the ability to not only protect neurons by blocking cell death but also by preventing inflammation.” This contrasts with tPA which works by removing blood clots and does not protect neurons.
Although none of the doses resulted in obvious side-effects in the rats, the laboratory will perform additional studies to determine if the drug is appropriate for clinical trials. Future studies will further examine how neuregulin-1 works from a molecular level. Given its ability to prevent inflammation, neuregulin-1 might also be a useful treatment for chronic inflammatory diseases such as arthritis, Dr. Ford says.
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.
*Xu Z, Croslan D, Harris A, Ford G, Ford B. “Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke.” Journal of Cerebral Blood Flow and Metabolism, advance online publication, August 31, 2005, doi:10.1038/sj.jcbfm.9600212.
-By Michelle D. Jones-London, Ph.D.
Last Modified January 31, 2007