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

Abstract

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 g/kg, i.v.) and TA0910 (100 and 400 g/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 g/kg, i.v.) had no significant effect. TRH (25-1600 g/kg, i.v.) and all three TRH analogs, CG3703 (6.25-400 g/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 g/kg, i.v.), and TA0910 (25-1600 g/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 T 3 and T 4 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.

Excitatory Effects of Thyrotropin-Releasing Hormone in the Thalamus

“…Importantly, clinical studies have identified TRH as an anticonvulsant in children with Lennox-Gastaut and West syndromes (Matsumoto et al, 1987;Takeuchi et al, 2001) and in animal models of epilepsy, including absence epilepsy (Ujihara et al, 1991;Momiyama et al, 1996). These likely represent central effects because, as also demonstrated for the sleep-modulating effects (Nishino et al, 1997), TRH doses sufficient to produce anticonvulsive protection do not significantly elevate peripheral thyroid hormone concentrations, and the anticonvulsant actions are not mimicked by activation of the thyroid axis (Nemeroff et al, 1975;Momiyama et al, 1996). TRH is distinct from most commonly used antiepileptic drugs because its actions may involve excitatory rather than inhibitory effects in the CNS (Takeuchi et al, 2001).…”

“…Indeed, intracerebroventricular administration of TRH dramatically reduces sleep time in rats (Hinkle et al, 2002). Furthermore, in canine narcolepsy, TRH analogs alleviate the hallmark symptoms of daytime sleepiness and cataplexy (Nishino et al, 1997). A site of action for these effects has not yet been described.…”

“…Furthermore, prominent TRH receptor (TRHR) expression occurs in thalamic relay nuclei (Cao et al, 1998;Heuer et al, 2000;O'Dowd et al, 2000). Yet despite the documented presence of signaling components, a role for TRH within the thalamocortical circuitry remains to be determined; however, clinical and experimental reports suggest that both ep-ileptic discharge and sleep can be modulated by TRH (Nemeroff et al, 1975;Matsumoto et al, 1987;Ujihara et al, 1991;Momiyama et al, 1996;Nishino et al, 1997).…”

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

“…Clinical data suggest that sleep can be modulated by TRH, 126 but the role of TRH in the regulation of sleep in humans has not yet been clarified. Hemmeter et al 127 examined the effects of pulsatile administration of TRH on the sleep EEG pattern and the nocturnal secretions of cortisol and GH in healthy male subjects.…”

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).…”