Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice.
Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.
Mieda
Michihiro
M
Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Willie
Jon T
JT
Hara
Junko
J
Sinton
Christopher M
CM
Sakurai
Takeshi
T
Yanagisawa
Masashi
M
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000627:therapeutic use*; D002385:Cataplexy / Q000517:prevention & control*; D017115:Catheter Ablation; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000235:genetics* / Q000628:therapy*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics* / Q000627:therapeutic use*; D000068797:Orexins; D011498:Protein Precursors / Q000235:genetics; D051381:Rats; D014851:Wakefulness / Q000187:drug effects*
D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011498:Protein Precursors