Brain chemical may help narcolepsy, study shows

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Replacing a missing brain chemical may help people with narcolepsy, a condition that causes patients to fall asleep involuntarily, U.S. researchers reported on Monday.

Tests on mice showed that injections of orexin, a message-carrying chemical, or neurotransmitter, that has been suspected in narcolepsy, helped the sleepy mice wake up.

"Assuming that narcoleptic humans are like these mice, which is a very plausible assumption, our experiments provide a strong proof of the concept that introducing into the brain a molecule that mimics the effect of orexin will be the fundamental cure for human narcolepsy,” said Dr. Masashi Yanagisawa, a professor of molecular genetics who led the study.

Yanagisawa and colleagues at the University of Texas Southwestern in Dallas tested mice they had genetically engineered to make no orexin.

Patients with narcolepsy have been found to have no or very little orexin in their cerebrospinal fluid, which suggests they may be deficient in the chemical.

Writing in the Proceedings of the National Academy of Sciences, Yanagisawa’s team said their genetically engineered mice did not wake up to feed as normal mice did, and they also experienced cataplexy, a sudden weakness in the muscles that accompanies narcolepsy.

“We believe these mice represent the closest model of human narcolepsy,” Yanagisawa said.

When injected with orexin, the mice woke up. And they did not then fall into a deeper sleep, a condition called “rebound sleep,” when the orexin effect wore off.

“This is extremely important because it shows that these mice retain the ability to respond to orexin,” Yanagisawa said.

The drugs used to treat narcolepsy now affect only the symptoms and all can have serious side effects. Stimulants such as amphetamines can be used to help sleepiness, while antidepressants are used against the cataplexy.

A drug called Provigil, made by Cephalon and also made generically, is approved for treating narcolepsy in the United States.

Any new drug therapies for narcolepsy would be based on developing molecules, called orexin receptor agonists, that mimic the effect of orexin and that are small enough to cross the blood-brain barrier, Yanagisawa said.

Such drugs might also help insomnia, he said.

It may also be possible to develop gene therapy to treat narcolepsy, adding orexin genes or transplanting cells that produce orexin.

SOURCE: Proceedings of the National Academy of Sciences, 2004.

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