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Recreating ’Flowers for Algernon’ with a happy ending

08.11.2005


UCLA scientists use statins to overcome learning disabilities in mice



In a surprise twist that recalls the film classic "Flowers for Algernon," but adds a happy ending, UCLA scientists used statins, a popular class of cholesterol drugs, to reverse the attention deficits linked to the leading genetic cause of learning disabilities. The Nov. 8 issue of Current Biology reports the findings, which were studied in mice bred to develop the disease, called neurofibromatosis 1 (NF1).
The results proved so hopeful, that the Food and Drug Administration approved the use of the drugs in three clinical trials currently under review to test the effect of statins in children and adults born with NF1. The findings could help the estimated 35 million Americans who struggle with learning disabilities.

"Learning disabilities and mental retardation each affect five percent of the world population," said Dr. Alcino Silva, professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. "Currently, there are no treatment options for these people. That’s why our findings are so exciting from a clinical perspective."



In an earlier study, Silva and his colleagues linked NF1’s learning problems to a protein called Ras, a protein that regulates how brain cells talk to each other. This communication is what enables learning to take place. The NF1 mutation creates hyperactive Ras, which disrupts cellular conversation and undermines the learning process.

"The act of learning creates physical changes in the brain, like grooves on a record," said Silva. "But surplus Ras tips the balance between switching signals on and off in the brain. This interrupts the delicate cell communication needed by the brain to record learned information."

The UCLA team began searching for a safe drug that would zero in on Ras and overcome its hyperactivity without causing harmful side effects over long-term use.

"It became something of a Quixotic quest -- an impossible dream," Silva admitted. "We thought, ’Wouldn’t it be nice to find a drug that is already FDA-approved, safe for lifetime use and could be tested in mice and humans with NF1?’ Fortunately, our optimism was rewarded."

It took a medical student in Silva’s lab to identify the drug and connect it with NF1. Steve Kushner, a scholar in UCLA’s MD/PhD program, learned in a clinical rotation about statins, the drugs already prescribed to millions of people worldwide to lower cholesterol.

"Steve raced into my lab and shared what he’d learned: statins work on the Ras protein that is altered by NF1 and play a key role in learning and memory," recalled Silva. "It was the researcher’s equivalent of finding a suitcase stuffed with a million dollars."

Statin drugs lower cholesterol by blocking the effects of certain fats. Because Ras requires fat to function, less fat results in less Ras. With reduced Ras activity, the brain cells are able to communicate properly in mice with NF1, allowing normal learning to take place.

"NF1 interrupts how cells talk to each other, which results in learning deficits," said Silva. "Statins act on the root of the problem and reverse these deficits. This enables the process of learning to physically change the brain and create memory."

Silva’s lab tested the effects of statins on mice that were bred with the NF1 mutation. The animals displayed the same symptoms as people with NF1: attention deficits, learning problems and poor physical coordination.

First author Weidong Lee, a UCLA postdoctoral fellow, ran three tests to compare the behavior of NF1 mice treated with statins to NF1 mice who received a placebo. Then he compared both groups to normal mice.

First, he trained the mice to follow a blinking light in order to find a food reward. The NF1 mice on statins showed a 30 percent improvement in their ability to pay attention, outperforming the normal mice.

Second, he trained the mice to memorize spatial clues in order to navigate a water maze and swim to a platform. The normal animals learned to find the platform in seven days; the NF1 mice took 10. After receiving statins, the NF1 mice outraced the normal mice.

Third, Lee tested coordination by training the mice to balance while running on a rotating log, which gradually increased in speed. At first, the NF1 mice would jump off as the log spun faster. But statin therapy enabled the NF1 mice to perform as well as their normal counterparts.

"This is mind-blowing – we think we have a real fundamental reason to be optimistic," explained Silva. "Here is a drug that affects a key learning and memory pathway, and completely rescues the most common genetic cause for learning disabilities. We don’t have to do extensive clinical trials for toxicity or safety – these were already completed for other uses."

Elaine Schmidt | EurekAlert!
Further information:
http://www.mednet.ucla.edu

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