Imagine you get nine hours of sleep every night, squeeze in long naps whenever you can, and yet every waking hour is a blur of exhaustion, poor focus and longing for the next time your head will hit the pillow. That is the reality for people with primary hypersomnia, a poorly understood, rare condition of perpetual sleepiness and lethargy.
The dogma in sleep science has been that unexplained sleepiness is caused by underactive brain regions involved in wakefulness and attention. This view has done little to provide relief for many of the chronically tired. Yet the opposite hypothesis—that the body might be producing a natural brake or sedative—has been controversial. Now scientists at Emory University have found just such a sedative in patients with primary hypersomnia, providing hope for the weary and perhaps even pointing to a new type of sleep-aid drug.
The Emory team discovered the sleep-promoting substance in the patients' cerebrospinal fluid, the watery liquid that cushions the brain and surrounds the spinal cord. In a study appearing in Science Translational Medicine last November, the researchers demonstrated that the compound enhances the activity of the same signaling pathway in the brain that is spurred on by sedatives such as the commonly prescribed benzodiazepines Valium and Ambien. The pathway involves gamma-aminobutyric acid (GABA), which is an attention-dampening neurotransmitter.
The researchers took spinal fluid from 32 patients with primary hypersomnia and applied it to human cells while measuring their electrical activity. They found the spinal fluid ramped up GABA receptor activity by some 84 percent, when GABA was also present (as it is in the brain). Spinal fluid from unaffected individuals enhanced GABA receptor activity, too, though to a lesser extent. There the boost was closer to 36 percent—similar to the effect elicited by patients' spinal samples after researchers removed the natural sedative.
The compound's chemical identity remains a mystery; thus far the researchers have determined that it is probably a peptide, which is a small protein. Future work will focus on identifying and perhaps even synthesizing the substance, to act as a sleep aid for people with insomnia.
For the perpetually sleepy, the recent work offers hope. Because their internal sedative acts in the brain like a benzodiazepine drug, the investigators reasoned that its action could be blocked by flumazenil, a drug given intravenously to treat benzodiazepine overdoses.
In seven hypersomnolent patients, flumazenil did restore alertness and reaction times for several minutes to a few hours, depending on the dose. For one of these patients—a woman who has managed to obtain an ongoing supply of the drug in tablet and cream forms—that relief has lasted four years.
Getting enough flumazenil to treat multiple individuals with hypersomnia may be tricky—the entire North American supply would be enough for only four hypersomniacs at the doses likely needed to maintain alertness all day, every day. Even so, Emory researchers have begun initial trials exploring the possibility of using the drug, or another like it, to awaken those living with internal sedation.
Number of Americans who have a chronic sleep disorder.
Estimated medical costs associated with sleep disorders in the U.S., which do not include indirect costs associated with lost productivity.
Number of sleep disorders described to date.
Average time it takes a person to fall asleep.
Number of drugs on the market for treating sleep disorders.
Amount of cerebrospinal fluid produced by the brain each day. This liquid keeps the brain buoyant and may also transport a newly discovered internal sedative.
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