Drug may counteract down syndrome

Researchers may have finally found a drug candidate for reducing the mental retardation caused by Down syndrome, which afflicts more than 350,000 people in the U.S. Researchers gave low doses of a human drug to mice bred to mimic the learning and memory problems in people with Down syndrome. After as little as two weeks, the impaired mice performed as well as normal ones in learning tests, and the improvement lasted for up to two months after treatment ended.

But there is a catch: the drug was taken off the market 25 years ago after being found to cause dangerous seizures in some people. And many compounds that boost learning in mice fail in human trials.

Nevertheless, "anyone studying Down's is going to have their socks blown off by this," says geneticist Roger Reeves, a Down syndrome specialist at the Johns Hopkins School of Medicine in Baltimore, who was not involved in the study. "There hasn't been anything out there that we really could take to patients or that we had a strong possibility of taking into the clinic."
Researchers tested the drug, pentylenetetrazole (PTZ), as well as two other compounds—picrotoxin and a gingko biloba extract called bilobalide—because they all interfere with tiny ion channels on brain cells (neurons). When activated, the channels, known as GABAA receptors, inhibit the cells, making it harder for them to form new synapses, or connections, with neighboring neurons.

The deficits of Down syndrome may occur because the brain contains too many such inhibitory signals, says Stanford University neurobiologist Craig Garner, whose group performed the experiments. "In order to learn, you have to have a period during which synapses can get stronger or weaker," he says. "This changing is what's not possible when you have too much inhibition."

So Garner, his student Fabian Fernandez, and their colleagues gave their mice either low doses of PTZ mixed with milk, or low-dose injections of picrotoxin or bilobalide, daily for two to four weeks to slightly raise the level of excitation in the brain. Immediately after treatment, the animals' scores on two memory tests—for recognizing objects they had seen before or remembering how they last entered a maze—were on par with normal mice; two months later, they still did much better than they normally would.

The treatment "is allowing the normal properties of neurons to work," Garner says. "This slowly over time leads to an improved circuit."

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