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Researchers Identify a Signal for Cell Death during Stroke

For release: Wednesday, March 3, 2010

In a new study, researchers have identified a signal that promotes the death of vulnerable brain cells in an animal model of stroke.  In the future, drugs designed to inhibit this death signal might help reduce brain damage in stroke patients.

“This study not only provides new insights into the cellular and molecular basis responsible for stroke damage, but also gives us a promising target for stroke therapy,” said Youming Lu, M.D., Ph.D., professor of neurology and neuroscience at the Louisiana State University Health Sciences Center School of Medicine in New Orleans.  Dr. Lu’s study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the American Heart Association.

Stroke is the third leading cause of death and a major cause of disability in the U.S.  Most strokes are ischemic – caused by a clot that restricts blood flow and oxygen to the brain.  An ischemic stroke leads to a harmful chain of events involving the brain chemical glutamate.  Glutamate signaling from one neuron to another is essential for brain function, but during ischemia, glutamate signaling is amplified and becomes toxic to neurons.

One possible strategy for treating stroke is to block the NMDA receptor, an ion channel (or pore) at the surface of neurons that is opened by glutamate.  Many drugs that block the NMDA receptor were tested in clinical trials in the 1990s, but failed to show benefit.  Because such drugs have the potential to interfere with wakefulness and breathing, they had to be tested at low doses – possibly too low to counteract glutamate’s toxic effects.

A more recent therapeutic strategy is to identify factors that contribute to glutamate toxicity but are not required for normal glutamate signaling.

As reported in Cell*, Dr. Lu and his team found a protein inside neurons that increases the opening of NMDA receptors and contributes to neuronal death during ischemia.  The protein was previously shown to promote cell death in other contexts, and was named death-associated protein kinase 1 (DAPK1).  In their study, Dr. Lu and his team found that DAPK1 interacts with a piece of the NMDA receptor called the NR2B subunit, which is thought to be especially important in glutamate toxicity.

In experiments in mice, the researchers tested whether they could reduce stroke damage by blocking DAPK1.  In one set of experiments, they bred mice lacking the gene for DAPK1.  Compared to control mice, the DAPK1-null mice had less evidence of neuronal degeneration and smaller areas of brain damage after an ischemic stroke.  Importantly, absence of the DAPK1 gene did not adversely affect normal brain function in the mice.

In another set of experiments, Dr. Lu and his team asked if they could block the interaction between the NMDA receptor and DAPK1 by using a custom designed molecule.  The researchers created a fragment of the receptor’s NR2B subunit, and attached it to a viral protein that would allow it to enter brain cells.  They predicted that this molecule would act as a decoy for DAPK1, and thus reduce the level of harmful glutamate signaling that occurs during an ischemic stroke.  Mice that were given intravenous injections of this molecule up to one hour after an ischemic stroke had smaller areas of damaged brain tissue compared to mice given a sham molecule.

The designer molecule paves the way for drugs that could target DAPK1 and reduce permanent brain damage in stroke patients.  Because DAPK1 does not appear to be required in the healthy brain, there is hope that DAPK1-targeted drugs will lack the side effects of the NMDA receptor blockers tested in the 1990s.

- By Daniel Stimson, Ph.D.

*Tu W et al.  “DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke.”  Cell, January 22, 2010, Vol. 140(2), pp. 222-234.

Last Modified March 3, 2010