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

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  • Author(s): Mieda M;Mieda M; Willie JT; Hara J; Sinton CM; Sakurai T; Yanagisawa M
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2004 Mar 30; Vol. 101 (13), pp. 4649-54. Date of Electronic Publication: 2004 Mar 16.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Intracellular Signaling Peptides and Proteins*; Carrier Proteins/*genetics ; Carrier Proteins/*therapeutic use ; Cataplexy/*prevention & control ; Narcolepsy/*genetics ; Narcolepsy/*therapy ; Neurons/*physiology ; Neuropeptides/*genetics ; Neuropeptides/*therapeutic use ; Wakefulness/*drug effects; Animals ; Catheter Ablation ; Disease Models, Animal ; Genetic Therapy ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Neurons/pathology ; Orexins ; Protein Precursors/genetics ; Rats
    • 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.
    • References:
      Eur J Neurosci. 2000 Feb;12(2):726-30. (PMID: 10712652)
      Lancet. 2000 Jan 1;355(9197):39-40. (PMID: 10615891)
      Neuron. 2000 Sep;27(3):415-8. (PMID: 11055422)
      Neuron. 2000 Sep;27(3):469-74. (PMID: 11055430)
      Annu Rev Neurosci. 2001;24:429-58. (PMID: 11283317)
      Sleep Res Online. 2000;3(1):23-8. (PMID: 11382896)
      Neuron. 2001 May;30(2):345-54. (PMID: 11394998)
      Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9965-70. (PMID: 11493714)
      Neurosci Lett. 2001 Nov 9;313(3):125-8. (PMID: 11682143)
      Regul Pept. 2002 Mar 15;104(1-3):11-20. (PMID: 11830271)
      Brain Res. 2002 Jul 12;943(2):224-36. (PMID: 12101045)
      Nat Neurosci. 2002 Nov;5 Suppl:1071-5. (PMID: 12403989)
      Ann Neurol. 2003 Feb;53(2):154-66. (PMID: 12557281)
      Neuron. 2003 Jun 5;38(5):715-30. (PMID: 12797957)
      Neuroendocrinology. 1976;22(1):57-71. (PMID: 1030786)
      Psychopharmacology (Berl). 1979;66(3):291-5. (PMID: 231278)
      Gene. 1991 Dec 15;108(2):193-9. (PMID: 1660837)
      Prog Neurobiol. 1997 May;52(1):27-78. (PMID: 9185233)
      J Pharmacol Exp Ther. 1997 Nov;283(2):757-69. (PMID: 9353396)
      Cell. 1998 Feb 20;92(4):573-85. (PMID: 9491897)
      J Neurosci. 1998 Dec 1;18(23):9996-10015. (PMID: 9822755)
      Biochem Biophys Res Commun. 1998 Dec 18;253(2):241-5. (PMID: 9878522)
      Brain Res. 1999 May 8;827(1-2):243-60. (PMID: 10320718)
      Cell. 1999 Aug 6;98(3):365-76. (PMID: 10458611)
      Cell. 1999 Aug 20;98(4):437-51. (PMID: 10481909)
      Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10911-6. (PMID: 10485925)
      Peptides. 1999;20(9):1099-105. (PMID: 10499428)
      J Neurosci. 2002 Sep 1;22(17):7754-65. (PMID: 12196599)
      Peptides. 2002 Sep;23(9):1683-8. (PMID: 12217429)
      Arch Neurol. 2002 Oct;59(10):1553-62. (PMID: 12374492)
      Nat Med. 2000 Sep;6(9):991-7. (PMID: 10973318)
    • Accession Number:
      0 (Carrier Proteins)
      0 (HCRT protein, human)
      0 (Intracellular Signaling Peptides and Proteins)
      0 (Neuropeptides)
      0 (Orexins)
      0 (Protein Precursors)
    • Publication Date:
      Date Created: 20040409 Date Completed: 20040719 Latest Revision: 20181113
    • Publication Date:
      20240829
    • Accession Number:
      PMC384801
    • Accession Number:
      10.1073/pnas.0400590101
    • Accession Number:
      15070772