Brain chemical could aid stroke treatment

Hopkins scientists see potential in treating degenerative illnesses

November 09, 1999|By Diana K. Sugg | Diana K. Sugg,SUN STAFF

Scientists have identified an unusual chemical messenger in the brain that appears to be involved in some key activities that make us human: feeling, thinking and remembering. The work could ultimately lead to treatments for stroke and degenerative diseases.

In a study published today in the Proceedings of the National Academy of Sciences, researchers from the Johns Hopkins University School of Medicine reveal the source of this newly identified substance, D-serine, and the novel way it works in the brain.

Typically, one nerve cell sends a message to another through a chemical messenger. But the new research found that D-serine works in tandem with another neurotransmitter to get the message delivered. One neurotransmitter, called glutamate, is released, apparently causing D-serine to be released. Together, they bond to their target. Mission accomplished.

This is important because glutamate is one of the most powerful and abundant of the brain's neurotransmitters. And, like all neurotransmitters, it is discriminating. It links only with certain targets, or receptors. It initiates learning and memory, experts say, by linking with a key receptor, but only when helped by D-serine.

"There is so much glutamate floating around in the brain, so God developed a fail-safe system," said Dr. Solomon H. Snyder, the Hopkins neuroscientist who led the research team. "It's like a lock that requires two separate keys."

Glutamate plays a major role in stroke damage. In a stroke, a blood vessel is blocked, cells can't get needed oxygen and glucose. This triggers a flood of glutamate, as much as 50 times more than normal. That overstimulates the receptors and kills brain cells.

Now that Snyder's group has isolated and cloned the enzyme that makes D-serine, researchers can begin to develop drugs that might inhibit production of it. The drugs would squelch activity at the receptors and stop brain damage.

Scientists say the work is significant.

"It's a whole system that was not previously known to have this important regulatory role. It wasn't known to be a player before," said Dr. Dennis Choi, head of neurology at Washington University in St. Louis and president of the Society for Neuroscience. "It's really a very powerful discovery whose implication will now have to be worked out in some more detail."

The identification of D-serine overturns many preconceptions about neurotransmitters.

D-serine's structure differs from that of any similar molecule found in mammals. Normally, amino acids of that kind have atoms that extend from the left side of the molecule. D-serine's extend from the right. Snyder compared finding this in humans to "finding a pterodactyl in your local pet shop."

Second, this neurotransmitter comes from an unexpected place, the glial cells, which support and nourish nerve cells, rather than from the nerve cells themselves, where neurotransmitters typically are secreted.

"This provides some of the strongest evidence to date that these glial cells are not really support structures but are dynamically involved in communication in the brain," said Dr. Paul Greengard, professor of molecular and cellular neuroscience at Rockefeller University. "It's a very exciting piece of work."

The strangeness of D-serine might make it easier for researchers to develop a drug to inhibit it.

The substance was discovered several years ago by Japanese scientists. Four years ago, Snyder's team reported evidence that it might be a neurotransmitter. This week's study gives definitive proof.

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