LSUHSC Research Yields Promising Stroke Treatment
For the first time, research led by Youming Lu, PhD, MD, Professor of Neurology and Neuroscience at LSU Health Sciences Center New Orleans School of Medicine, has identified a novel mechanism that may trigger brain damage during stroke and identified a therapeutic approach to block it. The work, funded by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), both of the National Institutes of Health (NIH), as well as the American Heart Association, will be published in the January 22, 2010 issue of the top tier journal, Cell, available online at 12:00 noon ET on January 21, 2010.
The work focuses on particular receptors for the neurotransmitter, glutamate, called NMDA (N-methyl-D-aspartate) receptors, which constitute the major subtype of glutamate receptors. NMDA receptors play a key role in communication among nerve cells in the brain. They perform a number of necessary functions including playing a role in learning and memory, but can also be involved in processes that cause brain cell death. Under normal conditions, signaling through NMDA receptors prevents the deleterious overload of cells with calcium, but during insults like stroke, this process is disabled. Calcium overload triggers multiple intracellular processes which result in irreversible death of brain cells. The research team discovered that an enzyme, DAPK1 (Death-Associated Protein Kinase 1), binds to a portion of the NMDA receptor, and acts as a specific "NMDA receptor cell death signal" during stroke. The researchers wanted to determine whether the process could be circumvented by disrupting the DAPK1-NMDA receptor binding, and they developed a high potency reagent to test. The reagent not only blocked DAPK1, protecting brain cells against stroke insults, but it did so without affecting other physiological functions of NMDA receptors.
To date, all stroke clinical trials targeting glutamate receptors have failed, largely because of their side effects, inefficient delivery through the blood-brain barrier, and/or a limited time window for therapeutic intervention.
"It is conceivable that this study not only provides new insights into the cellular and molecular basis responsible for stroke damage, but also provides a therapeutic target for stroke therapy," says Dr. Youming Lu, who is also a research scientist at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence.
According to the American Heart Association, stroke is the third leading cause of death in the United States and is a leading cause of serious, long-term disability. NIH-supported research suggests that about one in six Americans will experience a stroke at some point after age 65 and stroke is fatal in 10-20% of cases. Louisiana is in the "stroke belt," an eight-state region in the southeastern United States which one recent study found had a more than 40% higher stroke mortality rate than the rest of the nation.
"By determining that the interaction between the NMDA receptor NR2B subunit and DAPK1 kinase serves as a trigger for cell death during stroke, this research points to a new therapeutic approach for the treatment of stroke that may avoid the negative side effects that have plagued the development of stroke therapeutics to date." said Dr. Suzana Petanceska, of the NIA Division of Neuroscience. "Furthermore, the therapeutic significance of these findings may reach beyond stroke to other neurodegenerative diseases of aging."
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