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.