Narcolepsy is a chronic neurologic disorder featuring excessive daytime sleepiness. It isn’t a rare condition, although it is under-recognized and under-diagnosed. It is estimated to effect 1 in 2,000 people globally.
“Our work is an example of how basic research can lead to a potential new therapy for a disease,” said SRI Center for Neuroscience’s Thomas Kilduff, Ph.D.
Potential for Human Narcolepsy
His team found that a form of baclofen, R-baclofen, works in both mouse models much better than the leading FDA-approved therapeutic for narcolepsy. Baclofen, which has been available for more than 50 years, is a chemical compound that exists as a mixture of two isomers, designated R and S.
“The next step would be to perform a study in narcoleptic patients to determine its potential for treatment of human narcolepsy."
The onset of narcolepsy is usually during adolescence or later, though diagnosis may take more than a decade. This makes it difficult to study the disease’s progression. The lack of authoritative mechanisms to explain what goes askew in the brain’s ability to regulate sleep-wake cycles has resulted in drugs that only address the symptoms, instead of the underlying causes, of narcolepsy.
Ataxin Model Limitations
In the paper “Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function,” Kilduff and Black worked with researchers at five institutions in Japan to create a model of narcolepsy that better mimics the human disorder.
The existing model, dubbed “Ataxin mice,” has been in existence for more than 10 years. Although Ataxin mice have allowed researchers to study narcolepsy, one key constraint is that these mice are born with the deficiency of the neurotransmitter hypocretin that has been implicated in causing narcolepsy, whereas the onset of human narcolepsy typically occurs after puberty.
“The mouse model developed by Dr. Kilduff and his colleagues offers a new approach to study narcolepsy and to explore potential therapies for this devastating sleep disorder. This new model allows more precise control of the timing and extent of hypocretin/orexin neuron loss, and thus may better mimic human narcolepsy,” said Janet He, Ph.D., of the National Institute of Neurological Disorders and Stroke.
The research team genetically engineered mice in which the hypocretin neurons could be selectively eliminated at any age by removing an antibiotic in the mouse food. In the new “DTA” model, degeneration of hypocretin neurons can be begun after puberty. This causes the mice to exhibit the two major symptoms of narcolepsy: excessive daytime sleepiness and cataplexy, the brief loss of muscle tone experienced by most narcoleptics.
Sodium oxybate vs. Baclofen
A second paper, “GABAB Agonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy,” involved the team using the new DTA model and the Ataxin model to compare R-baclofen against gamma-hydroxybutyrate (GHB).
Sodium oxybate, the sodium salt of GHB, was approved by the FDA in 2002 as the only therapeutic for narcolepsy that simultaneously alleviates cataplexy, excessive daytime sleepiness and nocturnal sleep disruption. However, it is still unclear how this drug promotes its beneficial effects.
Scientists had supposed that GHB works through affecting brain cells that respond to a neurotransmitter known as gamma-aminobutyric acid (GABA), which chiefly functions to inhibit excitability and regulate muscle tone. To inestigate the mechanism of action of GHB, SRI researchers tested R-baclofen, which blocks the GABA receptors suspected to be the target of GHB.
It turned out that R-baclofen promoted sleep time and longer bouts of wakefulness during the appropriate times for mice while also suppressing cataplexy. GHB modestly reduced cataplexy and increased sleep intensity, but did not improve other symptoms of narcolepsy to the extent that R-baclofen did.
“The improvement in wakefulness that we observed after R-baclofen was a particularly unexpected and important finding,” said Black.
“R-Baclofen works better than GHB in these two mouse models, but it remains to be determined whether it will work better in humans,” Kilduff added. “Although baclofen is already known to be safe for use in humans, the dose that is effective for spasticity may be different than the dose of R-baclofen that has the potential to treat narcolepsy."
GABAB Agonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy Sarah Wurts Black, Stephen R. Morairty, Tsui-Ming Chen, Andrew K. Leung, Jonathan P. Wisor, Akihiro Yamanaka, Thomas S. Kilduff The Journal of Neuroscience, 7 May 2014, 34(19):6485-6494; doi:10.1523/JNEUROSCI.0080-14.2014
Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study ofNarcolepsy and Orexin System Function Sawako Tabuchi, Tomomi Tsunematsu, Sarah W. Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi,Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S. Kilduff, and Akihiro Yamanaka The Journal of Neuroscience, 7 May 2014, 34(19):6495-6509; doi:10.1523/JNEUROSCI.0073-14.2014