Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice.

Abstract

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.

• Authors: Michihiro Mieda, Jon T Willie, Junko Hara, Christopher M Sinton, Takeshi Sakurai, Masashi Yanagisawa
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 13 Pg. 4649-54 (Mar 30 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15070772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carrier Proteins
• HCRT protein, human
• Intracellular Signaling Peptides and Proteins
• Neuropeptides
• Orexins
• Protein Precursors

Topics

• Animals
• Carrier Proteins (genetics, therapeutic use)
• Cataplexy (prevention & control)
• Catheter Ablation
• Disease Models, Animal
• Genetic Therapy
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins
• Mice
• Mice, Transgenic
• Narcolepsy (genetics, therapy)
• Neurons (pathology, physiology)
• Neuropeptides (genetics, therapeutic use)
• Orexins
• Protein Precursors (genetics)
• Rats
• Wakefulness (drug effects)