Sep. 8, 2006 People who must stay awake for long shifts – soldiers, pilots, truckers, students, doctors, parents of newborns – may take comfort from new research showing that preventing the gas nitric oxide from building up in the brain may ward off the sleep urge.
The research, conducted by investigators from Children's Hospital Boston and the University of Helsinki (Helsinki, Finland), ties together previous observations about sleep and finds that nitric oxide production in a specific region of the brain – the basal forebrain – is both necessary and sufficient to produce sleep. The findings appear in two related papers in the August 18 issue of the Journal of Neurochemistry and the September 5 issue of the European Journal of Neuroscience.
"This understanding of sleep physiology should provide a completely new basis for the development of drugs to prevent excessive sleepiness or to promote sleep," says study co-author Paul Rosenberg, MD, PhD, a researcher in the Neurobiology Program at Children's Hospital Boston, and a physician in the Center for Pediatric Sleep Disorders at Children's and in the Sleep Disorders Center at Beth Israel Deaconess Medical Center.
In 1997, senior investigator Tarja Porkka-Heiskanen MD, PhD, now at the University of Helsinki, first showed that when cats are awake for prolonged periods, a compound called adenosine accumulates in their brains, ultimately producing sleep. Once asleep, adenosine levels gradually decline. Rosenberg had been studying how the brain regulates the accumulation of adenosine in the brain for over 10 years, and, in 2000, he and his colleagues demonstrated in brain cells from rats that adenosine's release is stimulated by nitric oxide. The two teams decided to collaborate.
Studying mildly sleep-deprived rats – kept awake for an extra three hours – they found that nitric oxide production in the basal forebrain, but not in other parts of the brain, increased, by 50 to 150 percent. When they injected compounds that inhibit nitric oxide production into this region of the brain, adenosine levels did not increase and sleep was completely abolished (one type of inhibitor abolished dreaming, or REM, sleep, and the other non-REM sleep). The results were identical when the researchers injected a compound that scavenges nitric oxide – mops it up and renders it inactive.
In contrast, when the basal forebrain was infused with a nitric oxide "donor" – an agent that boosts nitric oxide levels – during a normal sleep-wake cycle, adenosine levels increased and the rats fell into a sleep much like the "recovery" sleep that occurs after prolonged wakefulness. Blocking adenosine receptors with caffeine prevented this nitric-oxide-induced slumber.
Rosenberg sees the most pharmaceutical promise in developing drugs that prolong wakefulness by curbing production of nitric oxide or scavenging the gas once it's produced. The opposite – a sleeping pill made from nitric oxide donors -- would be much harder, he says, since these compounds would likely break down before ever reaching the brain. However, one of the ways nitric oxide promotes sleep is by stimulating production of a signaling molecule called cyclic GMP, and it may be possible to achieve the same effect by using drugs that block cyclic GMP's breakdown, Rosenberg says.
One surprise in the research was that the main message telling the brain to go to sleep probably does not come from neurons, but from neighboring glial cells, which appear to produce the greatest amounts of nitric oxide. Until recently, glial cells have been assumed to play only a supportive role in the brain. Rosenberg speculates that the molecules that turn on nitric oxide production in glial cells (as yet undiscovered) might provide additional targets for drug development.
The research was funded by the National Institutes of Health, the Academy of Finland, the European Union, the Finnish Medical Society and the Sigrid Juselius Foundation, and an ESRS Sanofi-Synthelabo Research Award.
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