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Volume 17, Number 16, Issue of August 15, 1997 pp. 6401-6408
Copyright ©1997 Society for Neuroscience

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

Received Nov. 16, 1996; revised May 20, 1997; accepted May 27, 1997.

Seiji Nishino, Janis Arrigoni, Jeff Shelton, Takashi Kanbayashi, William C. Dement, and Emmanuel Mignot

Sleep Research Center, Stanford University School of Medicine, Palo Alto, California 94304

The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 µg/kg, i.v.) and TA0910 (100 and 400 µg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 µg/kg, i.v.) had no significant effect. TRH (25-1600 µg/kg, i.v.) and all three TRH analogs, CG3703 (6.25-400 µg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 µg/kg, i.v.), and TA0910 (25-1600 µg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T₃ and T₄ levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

Key words: thyrotropin-releasing hormone; narcolepsy; cataplexy; rapid eye movement sleep; deep sleep; light sleep

This article has been cited by other articles:

				C. Broberger and D. A. McCormick Excitatory Effects of Thyrotropin-Releasing Hormone in the Thalamus J. Neurosci., February 16, 2005; 25(7): 1664 - 1673. [Abstract] [Full Text] [PDF]

				E. A. Nillni and K. A. Sevarino The Biology of pro-Thyrotropin-Releasing Hormone-Derived Peptides Endocr. Rev., October 1, 1999; 20(5): 599 - 648. [Abstract] [Full Text]

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