Navigation Links
Sleep researchers at SRI International identify promising new treatment for narcolepsy

MENLO PARK, Calif.May 7, 2014Neuroscientists at SRI International have found that a form of baclofen, a drug used to treat muscle spasticity, works better at treating narcolepsy than the best drug currently available when tested in mice.

According to the National Institute of Neurological Disorders and Stroke (NINDS), narcolepsy, a chronic neurologic disorder characterized by excessive daytime sleepiness, is not a rare condition, but is under-recognized and under-diagnosed. It is estimated to impact 1 in 2,000 people worldwide.

In back-to-back papers published in the May 7 issue of The Journal of Neuroscience, Thomas Kilduff, Ph.D., who directs the Center for Neuroscience within SRI Biosciences, Sarah Wurts Black, Ph.D., a research scientist in the Center for Neuroscience, and colleagues present a mouse model of narcolepsy that mimics the human disorder better than other models currently in use. Kilduff, Black, and the SRI team then used the new narcolepsy model alongside a standard model to investigate a novel therapeutic pathway and to identify a promising way of treating narcolepsy.

"Our work is an example of how basic research can lead to a potential new therapy for a disease," said Kilduff. 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."

In humans, narcolepsy onset is typically during adolescence or later, but diagnosis may take more than a decade, making it difficult to study the progression of the disease. The lack of definitive mechanisms to explain what goes awry in the brain's ability to regulate sleep-wake cycles has consequently yielded drugs that only address the symptoms, rather than the underlying causes, of narcolepsy.

In the first of the two papers, "Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function," Kilduff and Black teamed with colleagues at five institutions in Japan to generate a model of narcolepsy that better mimics the human disorder. The existing model, called "Ataxin mice," has been available for over 10 years. Although Ataxin mice have enabled researchers to study narcolepsy, an important limitation 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., program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

In collaboration with Professor Akihiro Yamanaka of Nagoya University in Japan, formerly an SRI International Fellow in Dr. Kilduff's laboratory, the research team genetically engineered a mouse in which the hypocretin neurons could be selectively eliminated at any age simply by removal of an antibiotic in the mouse food. In the new "DTA" model, degeneration of hypocretin neurons can be initiated after puberty, causing 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.

In the second paper, "GABAB Agonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy," Black, Kilduff and colleagues used 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 remains unclear how this drug exerts its beneficial effects.

It was suspected that GHB works by affecting brain cells that respond to a neurotransmitter known as gamma-aminobutyric acid (GABA), which primarily functions to inhibit excitability and regulate muscle tone. To study the mechanism of action of GHB, SRI Biosciences' researchers tested R-baclofen, which blocks the GABA receptors suspected to be the target of GHB.

The research team found that R-baclofen promoted sleep time and longer bouts of wakefulness during the appropriate times for mice and also suppressed 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," cautioned Kilduff. "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."


Contact: Dina Basin
SRI International

Related medicine news :

1. Exploding head syndrome -- a real but overlooked sleep disorder
2. Despite recommendations for safer sleeping, infant deaths persist
3. Many parents dont follow safe infant sleep practices
4. Many infants still not placed on their backs to sleep
5. Better sleep predicts longer survival time for women with advanced breast cancer
6. Study shows link between sleep apnea and hospital maternal deaths
7. Extreme sleep durations may affect brain health in later life
8. Sleep disorder linked to brain disease
9. Penn researchers find link between sleep and immune function in fruit flies
10. Study links severe sleep apnea to increased risk of stroke, cancer and death
11. Fruitfly study: Epilepsy drug target implications for sleep disruption in brain disorders
Post Your Comments:
(Date:11/27/2015)... ... November 27, 2015 , ... A simply groundbreaking television series, "Voices ... show that delves into an array of issues that are presently affecting Americans. Dedicated ... open dialogue, this show is changing the subjects consumers focus on, one episode at ...
(Date:11/27/2015)... ... November 27, 2015 , ... Keeping in mind challenges ... health and wellness consultation, has collaborated with a leading web-based marketplace for extra-curricular ... experienced by parents and bring advice from parenting experts within their reach. As ...
(Date:11/27/2015)... , ... November 27, 2015 , ... ... largest, most successful and prominent nonprofit healthcare organizations in the country. They have ... with various organizations, and helped advance the healthcare industry as a whole through ...
(Date:11/27/2015)... (PRWEB) , ... November 27, 2015 , ... Avid collector, ... Ann Arbor Michigan boxing style concert posters. This is one of Joplin's most famous ... Canterbury House at the University of Michigan in Ann Arbor. The According to Hawley, ...
(Date:11/26/2015)... ... November 26, 2015 , ... Patients at Serenity Point ... come together on Thanksgiving Day to share the things that they are most ... Serenity Point YouTube channel, patients displayed what they wrote on index cards, describing ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... 26, 2015 Research and Markets ( ... Wound Care Market by Type (Dressings, Therapy Devices, Active ... Facility, Out-Patient Facility), and Geography - Global Forecast to ... --> --> The purpose of ... forecast of the global advanced wound care market. It ...
(Date:11/26/2015)... November 26, 2015 ... "Self Administration of High Viscosity Drugs" report ... has announced the addition of the "Self ... their offering. --> Research and Markets ... the "Self Administration of High Viscosity Drugs" ...
(Date:11/26/2015)... , November 26, 2015 ... the addition of the  "2016 Future ... European Cell Surface Marker Testing Market: ...  report to their offering.  --> ... addition of the  "2016 Future Horizons ...
Breaking Medicine Technology: