TRH-R2 receptors do not mediate the wake-promoting effects of the TRH analogue taltirelin in rodents

LE Appel1, EA Shanks1, AP McCarthy1, BJ Eastwood1, MC Gernshengorn3, WF Seidel1, SW Hughes2, KA Wafford1. 1Eli Lilly, Surrey, UK, 2Vertex, Abingdon, UK, 3NIH, Bethesda, USA

Thyrotropin-releasing hormone (TRH) is a tripeptide synthesized in the hypothalamus and released into the hypothalamic-pituitary portal circulation to act on the pituitary. TRH is also found in other tissues, particularly within the central nervous system, where it plays an excitatory role. Rodents have two related G protein-coupled receptors for TRH, subtype 1 (TRH-R1) and subtype 2 (TRH-R2). Taltirelin (TA-0910) is a TRH analogue which mimics the physiological actions of TRH. It was initially believed that TRH-R2 receptors mediated the central effects of TRH (1). Recent data, however, suggests this may not be the case (2). We therefore investigated the role of TRH-R2 in basal sleep patterns and in mediating the response to taltirelin.

Experiments were performed in accordance with the Animal (Scientific Procedures) Act 1986. Adult male Wistar rats (250-320g) and adult male TRH-R2 knock out (KO) and wild type (WT) mice (29-45g) were implanted with a telemeter i.p. and with a custom cranial implant. After recovery animals were evaluated in the SCORE-2000™ bioassay, which allows continual measurement and vigilance state scoring of electro-encephalogram (EEG) and electromyogram (EMG) (cranial implant), locomotor activity and body temperature (telemetry).

We found that taltirelin dose dependently promoted wakefulness in Wistar rats when dosed 5 hours after lights on (CT-5) at 0.1, 0.3 and 1mg/kg by 109 ± 15.2, 181 ± 15.1, and 225.7 ± 15.2 minutes respectively and had a similar wake-promoting effect in WT mice. Normal circadian sleep/wake activity was unchanged in TRH-R2 KO mice, and the wake-promoting effects of taltirelin were unaffected. After dosing (CT-5) there was an increase in wake for KO at 0.3, 1 and 3mg/kg by 58 ± 10.7, 108 ± 10.9, and 147 ± 10.5 minutes respectively; and for WT all three doses by 55 ± 12.5, 102 ± 13.8, and 126 ± 12.8 minutes, respectively (repeated measures ANOVA p<0.001 for all) Other effects include rebound sleep, in the first dark cycle after dosing, in the rat, KO and WT mice. The increase in sleep in the mice and rats is consistent with the hypothesis that the wake promoting effect of TRH agonists are not mediated by TRH-R2.

References

1) Khomane KS et al, Expert Opin Ther Pat, 21, 1673:1691, 2011

2) Thirunarayanan DVM et al, Neuropsychopharmacology, 38(6), 950:956, 2013