Drug may treat mental symptoms of Down syndrome

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An old drug once used to study epilepsy can help improve learning in mice with a form of Down syndrome and also might help people, U.S. researchers said on Sunday.

The beneficial effects the drug, called pentylenetetrazole, or PTZ, continued for two weeks after treatment. This suggests the drug, like some other psychiatric drugs, can make long-term changes in the brain.

The finding, published in the journal Nature Neuroscience, also can help scientists understand what causes the mental retardation seen in Down syndrome patients.

“This treatment has remarkable potential,” said Craig Garner, a professor of psychiatry and a director of the Down Syndrome Research Center at California’s Stanford University.

“So many other drugs have been tried that had no effect at all,” Garner said in a statement. “Our findings clearly open a new avenue for considering how cognitive dysfunction in individuals with Down syndrome might be treated.”

Down syndrome is the most frequent genetic cause of mental retardation and occurs equally around the world, in about one in every 800 births. About 5,000 children born in the United States each year have Down syndrome.

It is caused by the presence of a third chromosome, known as chromosome 21. Most people have two copies of each chromosome and the additional activity of the genes on the third copy of chromosome 21 is believed to cause the symptoms of Down syndrome.

Symptoms range from moderate mental retardation to very mild disability. Many Down’s patients also have health problems, especially heart trouble.

Fabian Fernandez, a student in Garner’s lab, was exploring the possibility that the brains of Down’s patients are too strongly affected by a chemical called GABA, a neurotransmitter, or message-carrying chemical, that stops brain cells from becoming too excited.

DAMPING DOWN LEARNING

“In general, learning involves neuronal excitation in certain parts of the brain,” Garner said. “For example, caffeine, which is a stimulant, can make us more attentive and aware, and enhance learning.”

PTZ does this by causing more GABA to be available in the brain. Overdoing this process can cause seizures and PTZ was once used to study epilepsy. But it is no longer approved for use in people.

Fernandez gave daily doses of PTZ to mice specially bred to have many of the same genetic differences that cause Down syndrome.

“My idea was that it might be possible to harness this excitation effect ... to benefit people with Down syndrome,” Fernandez said.

He gave the drug to the mice and then gave them a maze test. Normal mice tend to explore first one arm of a T-shaped maze and then the other, while the Down mice are more random in their exploration.

But after 17 days of treatment, the drug made the Down mice explore and learn more like normal mice.

“Somehow the drug treatment creates a new capacity for learning,” Garner said.

More tests showed that daily doses were required for several days before any effect was seen, and the mice acted more normally for up to two months after the drug was stopped.

That may suggest the drug is changing brain structure, Garner said. His team may explore testing the drug or a similar compound in people as a possible treatment for Down syndrome.

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