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Narcolepsy research triggers myriad brain studies

By Carolyn Y. Johnson
Globe Staff / November 30, 2009

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Research into an unusual sleep disorder is unraveling what goes awry in the brains of people who fall prey to daytime sleep attacks - and shedding light on everything from addiction to appetite.

Work that began in sleepy dogs and mice has led to a significant advance in understanding narcolepsy, providing new insight into the ways in which sleep and wakefulness, eating, and addictive behaviors are linked. The work is pointing to potential therapies not only for people who are chronically sleepy, but also for the much larger numbers who have trouble sleeping at all.

At the root of this work is a fundamental brain chemical called orexin. Research over the past decade has shown that narcolepsy is caused by the loss of a type of brain cell that produces orexin. Scientists have found that the chemical also helps determine when we are asleep and awake and plays a role in regulating appetite and addiction.

Orexin “was only discovered in 1998,’’ said Dr. Tom Scammell, a neurologist at Beth Israel Deaconess Medical Center. “A lot of the work is related to sleep, but it’s also opened up these other areas.’’

His lab teases out the nuances of narcolepsy with some unconventional techniques - including tickling sleepy mice to keep them awake and feeding them Froot Loops. The anticipation of the sugary cereal triggers one of the most striking symptoms of the disease: a temporary loss of muscle control called cataplexy, causing mice to drop in their tracks. Using gene therapy, he restored orexin to the brains of mice who lacked it and found that it improves their ability to stay awake and reduces cataplexy.

“If we could get orexin into the brains of people with narcolepsy - and get it to the right places at the right times - we could, I think, completely cure this disease,’’ Scammell said. “It would be like giving insulin to diabetics.’’

But beyond narcolepsy, orexin has become a topic of interest for the multifaceted role it plays in the brain.

Two years ago, a study in the Journal of Neuroscience found that when a form of the chemical was given to sleep-deprived rhesus monkeys, it restored their brain activity and improved their performance on a cognitive task.

Pharmaceutical companies are looking at whether a drug could be developed to treat the opposite problem, insomnia, by blocking the activity of orexin in the brain. Last year, GlaxoSmithKline paid an initial $150 million for a collaboration with Actelion, a Swiss company developing such a drug, as part of a larger agreement to pay as much as $2.7 billion - depending on whether the drug meets certain milestones. Merck is also developing such a drug, now in clinical trials.

Other research has pointed to the potential role orexin could play in addiction: Research has found that blocking orexin in mice decreases their drug-seeking behavior.

Finally, a study published in Cell Metabolism this year found that giving mice more orexin helped them resist obesity when given a high-fat diet, by reducing how much they ate and raising their energy expenditure.

The work that revealed the critical role that orexin plays in narcolepsy began almost by chance. Two groups independently discovered it in 1998.

Dr. Masashi Yanagisawa, a professor at the University of Texas Southwestern Medical Center, decided to test what would happen to mice that lacked orexin. (Orexin comes from the Greek word for appetite, “orexis’’.)

At first glance, the experiment was disappointing - there was no significant difference in the eating and weight of the mice. Then, he asked a researcher to watch the mice at night.

“Accidentally, we instead found out these mice just go around and suddenly they stop and they fall to the side, and suddenly are completely immobile for a minute, and then really it looks as if they’re dead,’’ Yanagisawa said. “Then suddenly, as if nothing has happened, they wake up. We were every surprised.’’

Simultaneously, Stanford University researchers studying narcoleptic dogs that would fall down when they ate - their muscles giving out when they were excited - found that a genetic defect in the orexin system was responsible.

Research confirmed that human narcoleptics also lack orexin, and scientists discovered that narcoleptics aren’t born lacking the cells that produce orexin; they die off over time. Researchers are still trying to understand what causes those cells to die, often causing the disease to affect patients as young adults.

That was the case for Julie Flygare, one of Scammell’s patients. In college, the varsity squash player blamed her exhaustion on her rigorous workout. Later, in law school, she assumed she couldn’t stay awake because she found a topic boring.

Flygare compares it to a person whose eyesight starts to decline, but doesn’t realize it because she doesn’t know how everyone else sees.

Around the same time, she began to notice that when she was about to tell a joke or laugh, she would sometimes feel her jaw freeze or her knees give out. Eventually, she got a diagnosis that made sense, and takes medications four times a day.

The drugs help, but there is no cure, and she still has to nap twice a day. She tries not to let the disease control her life, but Flygare has to be cautious about things like swimming, because her cataplexy could cause her to drown. And she is coming to terms with the realization that a career in law, requiring young attorneys to work intense hours, may not be in the cards.

“I assumed there was going to be great medications and they would make me better,’’ said Flygare.

Current therapies “don’t completely normalize you by any means,’’ she said. “That was weird for me. . . . I used to pride myself on being the person who can stay up until two in the morning and get a lot done.’’

Carolyn Y. Johnson can be reached at cjohnson@globe.com.