Old Monkey Study Might Help Old Human Brains

Molecule found that improves cortical function

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By
HealthDay Reporter

THURSDAY, May 1, 2003 (HealthDayNews) -- "I wanted to study old primates," says Audie G. Leventhal, "because I am an old primate."

And so starts a story that involves a colony of nonagenarian Chinese monkeys, a chemical that can help old monkey brains work better, and the University of Utah applying for patents on existing drugs that might help old human brains work better.

Leventhal, who at 53 is closer to a middle-aged primate, is a professor of neurobiology at the University of Utah School of Medicine. He also is an honorary professor at the University of Science and Technology in Anhui, China, a connection that came about because a number of his graduate students have been Chinese and he did a sabbatical there.

That is how he came to hear about the old macaque monkeys, which live in a colony in Kunming that was established in the 1950s as part of joint Chinese-Russian research program. They are about 30 years old, which translates into the human equivalent of 90 years, considering their shorter life span.

They look and act like 90-year-old humans, Leventhal says: wrinkled, balding, arthritic, toothless and slow on the uptake. They were the perfect subjects for Leventhal's program. "I was trying to figure out what we knew about cortical function in old primates," he says. "No one did it before."

Specifically, he looked at vision, which is controlled by a part of the cortex, the segment of the brain that also controls whatever higher intelligence monkeys (and humans) have. As described in a paper in the May 2 issue of Science, Leventhal and his colleagues focused on V1 neurons, brain cells that respond only to the sight of objects at a specific orientation or moving in a certain direction.

As they recorded the activity of those neurons while the monkeys watched images on a computer screen, the researchers also released small amounts of a chemical called gamma-aminobutyric acid (abbreviated as GABA), a neurotransmitter that helps control brain cell function. At various times, they also released a compound that enhances GABA activity and one that blocks it.

What they found is that brain cells in the old monkeys have lost much of their ability to respond to the specific signals carried by GABA. Giving GABA to young monkeys did very little in terms of brain function, but it helped the old monkeys a lot, Leventhal says.

"The analogy would be a street in New York that has computer-controlled lights to regulate traffic," he says. "In an old monkey, the system doesn't work as well, because the cells respond indiscriminately to traffic patterns, so traffic comes to a standstill."

GABA restored selectivity, so the cells worked better. So did the compound that increases the effect of GABA -- a GABA agonist, in scientific terms.

What's true for vision probably is true for other functions controlled by the cortex, Leventhal says: "GABA is found throughout the brain, so if GABA function is diminished, brain function is diminished."

Now he has started a research program aimed at identifying a drug that will help old human brains work better.

"First we must expand the range of drugs we look at," he says. "We can deliver GABA agonists that are already in existence directly to the cells. When we find the drug that has the best effect, then we deliver it systemically to the animals." (Systemically means in pill form or injection, rather than directly into the brain.)

"Then we train the monkeys to see if we can improve their performance, then we can see whether it helps humans. We now are in the process of testing various drugs," he says.

The drug used in the trial reported in the journal is mucimol, which is in clinical trials as a treatment for epilepsy. It works better than GABA -- too well, Leventhal says, overexciting the neurons.

But a number of other GABA agonists are available, and the university is writing patent applications for some of them, he says, as well as for GABA-like compounds. An existing drug might fill the bill. Alprazolam, whose brand name is Xanax and is marketed to treat anxiety and panic disorder, might be one of them, Leventhal says, and there are many more GABA agonists to be tested.

More information

A primer on how neurotransmitters work is offered by Mexico's Institute of Cellular Physiology. Learn more about age and health from the National Institute on Aging.

SOURCES: Audie G. Leventhal, Ph.D, professor, neurobiology, University of Utah School of Medicine, Salt Lake City; May 2, 2003, Science

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