In the genetic rescue, the researchers made transgenic, or genetically engineered, mice that not only lacked the orexin-producing neuron, but also continuously and diffusely expressed orexin everywhere in their brains. The mice did not experience any sleep abnormalities or cataplectic arrests, and they were able to maintain wakefulness.
Dr. Yanagisawa noted, however, that the transgenic mice never really experienced the orexin deficiency state because, even though they had no orexin-producing neurons, they had orexin in their brains from birth. That prompted a second experiment, in which the brains of orexin neuron-ablated mice were injected with orexin peptides.
"No one had done this before," Dr. Yanagisawa said. "In order to strengthen our argument, and also looking toward possible future medical treatments, we tried to pharmacologically rescue the mice."
The researchers found that the orexin injections increased wakefulness and suppressed cataplectic arrests. Also, there was no "rebound sleep" after the orexin effect wore off.
"This is extremely important because it shows that these mice retain the ability to respond to orexin," Dr. Yanagisawa said. "The downstream pathways, including the orexin receptors, are normal even in the absence of orexin-producing neurons. Also, the mice wake up, but do not try to regain that lost sleep, which is important with respect to therapeutic applications."
Wild-type mice that received the injection also woke up, but the waking up effect was more pronounced in the orexin neuron-ablated mice.
Dr. Yanagisawa said 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 bar
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Contact: Amanda Siegfried
amanda.siegfried@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
15-Mar-2004