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Treatments for Narcolepsy
SRI sleep researchers are discovering and developing new treatments for narcoleptic patients.
Narcolepsy is a neurological disorder that affects approximately 1 in 2,000 people worldwide. It is characterized by excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and a cluster of other symptoms related to an abnormality in rapid eye movement (REM) sleep.
The disorder was originally described in 1880, but its etiology was unknown until 2000, when two groups discovered a massive loss of hypocretin (Hcrt; also called orexin) neurons in the hypothalamus of narcoleptic patients. Working with researchers at the Scripps Research Institute, SRI's Dr. Thomas Kilduff co-discovered the hypocretin (Hcrt) peptides.
SRI’s Center for Neuroscience is engaged in three related projects for the National Institutes of Health. They are briefly described below.
Hypocretin Agonists as Treatment for Narcolepsy and Sleepiness
Because narcolepsy appears to be a neurodegenerative disorder in which Hcrt-containing neurons specifically degenerate, the goal of this research project is to discover and develop a novel hypocretin receptor (HcrtR) agonist to treat narcoleptic patients without the side effects of current drugs.
Current narcolepsy treatments are symptomatic and have a lot of room for improvement. Anticholinergics treat cataplexy, but have such undesirable side effects that patients often elect to live with this symptom. The debilitating EDS has been treated with amphetamine and other stimulant medications, which have abuse potential. More recently, gamma-hydroxybutyrate has been approved to treat both cataplexy and EDS, but the drug is a controlled substance.
Because HcrtRs are involved in multiple physiological functions, including arousal, pain, anxiety, and reward, drugs that target the Hcrt system could be used to treat other neurological and neuropsychiatric disorders, in addition to sleepiness, insomnia, and jet lag.
The project described was supported by Award Number R21NS062168 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.
TAAR1 Agonists as Narcolepsy Therapeutics
Although narcolepsy results from degeneration of neurons that produce Hcrt, no small-molecule brain-penetrable Hcrt receptor agonists currently exist for hypocretin replacement therapy. Current treatments include controlled substances with abuse potential or drugs with other undesirable side effects.
In papers published with scientists from F. Hoffmann-LaRoche, SRI researchers describe novel, brain-penetrable agonists for Trace Amine-associated Receptor 1 (TAAR1). These compounds cause a dose-dependent increase in wakefulness, reduce REM sleep, and have pro-cognitive, antidepressant-, and antipsychotic-like properties. This suggests TAAR1 as a novel target for the treatment of pathological sleepiness in addition to neuropsychiatric disorders.
SRI is working to determine the therapeutic efficacy of TAAR1 agonism as a treatment for narcolepsy in proof-of-concept studies using two murine narcolepsy models.
The project described was supported by Award Number 1R21NS083639-01 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.
Neurobiological Studies of Gammahydroxybutyrate
Gammahydroxybutyrate (GHB) has profound effects on the activity of the central nervous system, particularly on consciousness. Because of its sleep-inducing effects, GHB has become both a drug of abuse and, paradoxically, a clinically useful therapeutic for treatment of narcolepsy.
The U.S. Food and Drug Administration has approved Xyrem, the sodium salt of GHB, for the treatment of both the cataplexy and EDS symptoms of narcolepsy. GHB facilitates slow wave activity (SWA) in the EEG and slow wave sleep (SWS), thereby consolidating nocturnal sleep and resulting in increased alertness on the subsequent day.
SRI researchers are seeking to identify the neural substrates of GHB-induced SWA and understand the mechanism(s) underlying the therapeutic effects of GHB on narcolepsy/cataplexy. Study results will enhance our understanding of the neurobiology that underlies the therapeutic activity of GHB and may also provide insights into the cellular and molecular mechanisms that underlie cataplexy and EEG SWA.
The project described was supported by Award Number 5R01NS057464 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.