New Picture of Cell Death in Stroke

Finding could open way to better drug treatment

WEDNESDAY, Dec. 24, 2003 (HealthDayNews) -- Researchers say they have achieved a better understanding of how brain cells are killed by a stroke, one they think will lead to a new drug treatment to limit brain damage.

Until now, neuroscientists have thought the major culprit in nerve cell death when a stroke cuts off blood flow to a part of the brain is glutamate, an amino acid that carries signals from cell to cell. The release of glutamate by injured cells was supposed to open a channel that allowed a fatal flood of calcium ions into the nerve cells.

"But five years ago, when it became evident that antagonists to glutamate receptors were not working as a treatment for stroke, my laboratory went back to the drawing board," says Dr. Michael Tymianski, an associate professor of surgery and physiology at the University of Toronto.

Working at the Krembil Neuroscience Centre of Toronto Western Hospital, Tymianski and his colleagues have outlined a different scenario. Activation of a separate channel, called TRPM7, causes production of toxic molecules called free radicals that kill the brain cells, they report in the Dec. 26 issue of Cell.

The hope is the discovery could produce an effective drug treatment to save brain cells in the minutes after a stroke, Tymianski says. His timetable: a testable drug treatment just three years from now.

"We have done this kind of thing before, and the principles that underlie making a medication have been sorted out by us," he says. "We will now focus on developing medications that we can inject into stroke patients up to several hours after a stroke."

One widely used method of exploiting such a breakthrough in understanding is to go through a vast library of chemicals, hoping to find one with the desired action. Tymianski say this tedious process will not be necessary.

"We have some experience with a more targeted approach," he says. "Our studies have shown which proteins interact with these channels, and we can work on modulating these interactions."

The discovery is "a good example of how to have a strong partnership between clinical practice and basic research," says Dr. John MacDonald, chairman of the department of physiology at the University of Toronto. "My laboratory is a center of basic science and he is a neurosurgeon. Together, our efforts are directed toward solving clinical problems."

But the laboratory results must be tested in the real world, MacDonald says. "The whole concept that blocking glutamate channels in the brain would prevent stroke damage worked well in animals, but it did not pan out in human work," he says.

Nevertheless, Tymianski already has a picture of the kind of drug he wants to develop. "The ideal medication would have such a low side effect profile that it could be used as part of an emergency response by a paramedic," he says.

Identification of the TRPM7 channel is the key to such a drug, Tymianski says. "What we've done is plug a big hole in our understanding of cell death," he says. "This explains why previous approaches have failed. Now we believe we have the right target for a medication."

More information

You can learn about drugs being tested against stroke from the Internet Stroke Center, while the American Stroke Association explains brain attacks.

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