Brain Chemical Closely Tied to Narcolepsy

Mouse study finds transmitter orexin can reverse sleep disorder

MONDAY, March 15, 2004 (HealthDayNews) -- A mouse study cements a link between narcolepsy and a chemical that serves as a brain messenger.

Narcoleptic mice that were given the neurotransmitter orexin were miraculously cured of the disease. The mice had previously been stripped of their ability to produce the chemical.

The feat essentially proves a cause-and-effect relationship between orexin and narcolepsy.

"It's the final nail," says Dr. Masashi Yanagisawa, a professor of molecular genetics at the University of Texas Southwestern Medical Center in Dallas and an investigator at the Howard Hughes Medical Institute. "Knocking out orexin neurons causes narcolepsy, and giving it back cures it."

Yanagisawa was the senior author of the paper outlining these findings that appears in this week's issue of Proceedings of the National Academy of Sciences.

Although the concept still needs to be tested in humans, Yanagisawa says, "now it's very well proven that the vast majority of human patients do have orexin deficiency, just like the mice."

Scientists are also hopeful the finding will eventually lead to a treatment for narcolepsy in humans and possibly also an aid to help insomniacs stay alert and awake during the day.

"These are very exciting results, very carefully done and promising," says Dr. Seiji Nishino, associate director of the Center for Narcolepsy at Stanford University School of Medicine in California.

Orexin is produced by neurons in the hypothalamus region of the brain. Previous research had demonstrated that when the orexin gene is disrupted or orexin-producing neurons destroyed, mice showed symptoms of narcolepsy. People (and mice) who suffer from this rare disease fall asleep uncontrollably, are excessively sleepy during the day, and also have sudden muscle weakness. There is no cure, only symptom-oriented treatments with many side effects.

In this experiment, researchers injected orexin peptides into the brains of mice who could not produce orexin on their own. The injections increased wakefulness and also reduced episodes of muscle weakness. There was also no "rebound sleep," which often happens after drugs such as amphetamines are used to counteract the symptoms of narcolepsy.

Now the question is how to get these benefits from mice to humans. One thing is clear: Orexin itself is not going to do it.

"We found that orexin itself can correct the mouse disease, that much is pretty sure," Yanagisawa. "However, the problem is orexin itself cannot be administered orally and, even if you inject it like insulin, it will not go into the brain because of the blood-brain barrier."

"The idea is to supply the chemical, like for diabetes, but the problem is that the chemical is a very large molecule, so it doesn't go into the brain," Nishino adds.

The good news is that the particular class of receptor to which orexin receptors belong to are the best drug targets. "If you count all of the best-seller drugs currently in use in clinics, more than half of them actually target one or more of these receptors," Yanagisawa says.

If an orexin-look-alike compound could be found, another advantage would be that it would impose a "physiological wakefulness" as compared with speed or other stimulants currently in use. "They basically hit a wide variety of neurons in a very nonselective way and force your brain to wake up," Yanagisawa says. "Compared with that, an orexin receptor agonist will induce physiological wakefulness even in normal mice."

This raises the hope that such a treatment will also benefit people with insomnia, a much larger group than those with narcolepsy. "What insomniacs really complain about is actual daytime sleepiness, lack of energy," Yanagisawa explains. "At least in theory, if you have this small compound, you can take one pill during the morning and that will boost energy and attention and, by the evening, the drug's effects will wear off. That's the scenario, and I think that's very likely to work."

More information

For more on narcolepsy, visit the Center for Narcolepsy at Stanford University. The National Sleep Foundation has more on insomnia.

SOURCES: Masashi Yanagisawa, M.D., Ph.D., professor, molecular genetics, University of Texas Southwestern Medical Center, Dallas, and investigator, Howard Hughes Medical Institute; Seiji Nishino, M.D., Ph.D., associate director, Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, Calif.; March 15-19, 2004, Proceedings of the National Academy of Sciences
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