Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

Abstract

The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of Human narcolepsy is a chronic life-long disorder characterized by excessive daytime somnolence (EDS), abnormal manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis), and cataplexy (Aldrich 1992;Guilleminault 1994;. Cataplexy is a sudden loss of muscle tone in response to emotionally-exciting stimuli. It is akin to the muscle atonia that occurs during physiological REM sleep, but it occurs inappropriately during wakefulness (Aldrich 1992;Guilleminault 1994;. The current treatments for narcolepsy require the use of central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). These treatments, however, are often unsatisfactory due to incomplete therapeutic efficacy, the occurrence of various side effects, and the rapid development of drug tolerance (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). It is therefore necessary to explore more efficacious compounds with different pharmacological profiles for possible use in narcolepsy treatment.Canine narcolepsy is a naturally-occurring animal model of the human disorder. Like humans, narcoleptic canines exhibit short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1998c;Riehl et al. 1998). Narcolepsy in Doberman pinschers and Labrador retrievers is caused by mutations in the gene encoding a receptor ( Hcrtr-2 ) for a novel neuropeptide, the hypocretins (orex- Received July 27, 1999; revised November 10, 1999; accepted December 23, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 1 CG-3703, a TRH Analog, in Narcoleptic Dogs 35 ins) (Lin et al. 1999). Human and canine narcolepsy share similar pharmacological characteristics (see for a review). This model is thus an invaluable resource for the study of the pathophysiology and treatment of narcolepsy. To this end, the canine model has been used in numerous pharmacological experiments to dissect the mode of action of various compounds on their effects on wakefulness and cataplexy, and to screen new compounds for use as possible treatments for narcolepsy (see for a review).Thyrotropin releasing hormone (TRH) is a tripeptidic hormone (L-pyroglutamyl-L-histidyl-L-prolineamide) originally extracted from the hypothalamus (Boler et al. 1969). It is now known to be distributed widely in the CNS, with receptors reported to exist in structures such as the pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al. 1989 for reviews). Besides its role in stimulating the release of thyroid stimul...

Excitation of Histaminergic Tuberomamillary Neurons by Thyrotropin-Releasing Hormone

“…Clinical and experimental reports demonstrated a role of TRH in the modulation of locomotion, cognition, mood, and sleep. Biologically stable TRH analogues such as CG3703 (montirelin) and TA0910 increase wakefulness and decrease sleep time in narcoleptic canines (Nishino et al, 1997;Riehl et al, 2000). TRH analogues are also known as antiepileptics in animal seizure models (Nillni and Sevarino, 1999) and in clinical use (Kubek and Garg, 2002).…”

Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men

“…Among many other features, it has CNS-stimulant and -antidepressant effects (18,29). Interestingly, chronic administration of a TRH analog increases wakefulness and ameliorates cataplexy in narcoleptic dogs (50), which may imply that diminished TRH tone is involved in the pathogenesis of these narcoleptic symptoms. However, the fact that circulating prolactin levels are normal in narcoleptic humans (unpublished observation) argues against (but does not exclude) a primary TRH deficiency in these patients, as TRH is involved in the regulation of prolactin release.…”

Therapeutics of Narcolepsy

“…TRH and agonists improve wakefulness and decrease cataplexy episodes in canine narcolepsy models. 100,170 Skin temperature regulation is dysfunctional in narcoleptics, possibly due to hypocretin deficiency. Manipulating cutaneous temperature can alter vigilance, sleepiness, and sleep architecture in patients with narcolepsy.…”