Retarded mice get smarter with drug

Retarded mice get smarter with drug
Down syndrome researchers see promise in PTZ, or pentylenetetrazole.
By Denise Gellene, Times Staff Writer
February 26, 2007

http://www.latimes.com/features/health/medicine/la-sci-down26feb26,1,6272157.story?coll=la-health-medicine

Lab mice with the mental retardation of Down syndrome got smarter after being fed a drug that strengthened brain circuits involved in learning and memory, researchers reported Sunday.

After receiving once-daily doses of pentylenetetrazole, or PTZ, for 17 days, the mice could recognize objects and navigate mazes as well as normal mice did, researchers said. The improvements lasted up to two months after the drug was discontinued, according to the report in the journal Nature Neuroscience.

Scientists said the study opened a promising avenue for research in a field that had seen little success.

"These mice are essentially restored to normal, which I haven't seen before," said David Patterson, a Down syndrome researcher at the University of Denver, who was not involved in the study. "And the treatment seems to be long-lasting, which is a pretty surprising observation all by itself."

Senior study author Craig C. Garner, a Stanford School of Medicine professor, said his lab was preparing to conduct human trials of the drug, although he said it would take time to complete more preliminary studies and procure a supply of purified PTZ.

People with Down syndrome should not be given the drug until it has been studied further, he cautioned, because PTZ can induce seizures at high doses and might have other serious side effects.

Down syndrome is a genetic disorder caused by an extra copy of chromosome 21. The syndrome occurs in one of 660 births and usually causes cognitive deficits, cardiac problems and physical abnormalities, such as low muscle tone, short stature and an upward slant to the eyes. More than 300,000 Americans have Down syndrome, making it the leading cause of mental retardation. There is no approved drug to improve cognition in people with Down syndrome.

PTZ blocks a neurotransmitter called gamma-aminobutyric acid, researchers said. GABA, as it is called, passes messages between neurons along specific brain pathways. Normal brains have a balance of neurotransmitters that excite neurons and make learning possible, and of GABA, which slows neurons down so they do not become overly stimulated. It is believed that people with Down syndrome have too much GABA, inhibiting brain circuits involved in learning and memory.

The drug was used until 1982 to enhance cognition in the elderly and mentally impaired people, but was removed from the market by the Food and Drug Administration because studies showed no clear benefits. Garner said he believed the drug failed in part because the dosing schedule then was different from the one his team used in mice.

The mice were genetically altered to possess cognitive impairments similar to those of Down syndrome patients.

Tests compared the mental abilities of mice fed PTZ against healthy mice and untreated altered mice.

Researchers said the drug took effect after several days. Once established, the improvements were long-lasting, although after three months the circuits in the brain showed a decline in activity, Garner said.

Scientists also fed PTZ to normal mice, but the drug had no effect on the animals' mental skills.

Stanford graduate student Fabian Fernandez, who designed the experiment, said the 17-day dose in mice was equivalent to a two- to three-year daily regimen in people. If the drug worked in humans as it did in mice ?- and there was no assurance it would ?- PTZ could produce cognitive improvements lasting up to 10 years, he said.

Professor Lynn Nadel, a Down syndrome researcher at the University of Arizona who was not involved in the research, said: "These results are very encouraging that it will ultimately be possible to do something to improve outcomes in Down syndrome."

Fernandez said the effect of PTZ on the mice prompted his Stanford colleagues to tease him that he was recreating the popular 1966 book "Flowers for Algernon," in which a fictional mouse masters mazes after an experimental surgery, then reverts when the effect wears off. Fernandez said researchers almost referred to the book in their study, but decided against it because their mice fared better than Algernon.

The book was adapted into the 1968 movie "Charly," for which Cliff Robertson won a best actor Oscar.

The research was sponsored by the National Institutes of Health and several foundations, including the Down Syndrome Research and Treatment Foundation, which was started in Silicon Valley by parents of children with Down syndrome.

Patricia A. O'Brien White, a co-founder of the foundation, said medical advances since the 1980s had more than doubled the life span of people with Down syndrome, to 56, increasing the likelihood that they would outlive the parents who cared for them. A small gain in cognition would allow a significant number of people with Down syndrome to hold jobs and live independently, she said.

"Typically the message that parents receive when the child is born is that nothing can be done," White said. "I think this study offers a different perspective."

The next test will be performed using hamsters.