Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

Abstract

Thyrotropin-releasing hormone receptor type 2 (TRH-R2), not TRH-R1, has been proposed to mediate the CNS effects of TRH and its more effective analog taltirelin (TAL). Consistent with this idea, TAL exhibited higher binding affinity and signaling potency at mouse TRH-R2 than TRH-R1 in a model cell system. We used TRH-R1 knockout (R1ko), R2ko and R1/R2ko mice to determine which receptor mediates the CNS effects of TAL. There was no TRH-R1 mRNA in R1ko and R1/R2ko mice and no TRH-R2 mRNA in R2ko and R1/R2ko mice. Specific [ 3 H]MeTRH binding to whole brain membranes was 5% of wild type (WT) for R1ko mice, 100% for R2ko mice and 0% for R1/R2ko mice, indicating TRH-R1 is the predominant receptor expressed in the brain. In arousal assays, TAL shortened sleep time with pentobarbital sedation in WT and R2ko mice by 44 and 49% and with ketamine/xylazine sedation by 66 and 55%, but had no effect in R1ko and R1/R2ko mice. In a tail flick assay of nociception, TAL increased response latency by 65 and 70% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. In a tail suspension test of depression-like behavior, TAL increased mobility time by 49 and 37% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. Thus, in contrast to the generally accepted view that the CNS effects of TAL are mediated by TRH-R2, these effects are mediated primarily if not exclusively by TRH-R1 in mice. Neuropsychopharmacology (2013) 38, 950-956;

Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue

“…Adult male and female wild-type (WT) and mice lacking the TRH 1 (R1KO), TRH 2 (R2KO), or both TRH 1 and TRH 2 (R1R2KO) receptor (10–11 weeks old at the start of experiments) were used for the indicated TFT and serum hormone analysis. The TRH receptor knockout and WT mice were bred in our colony for these studies and have been previously characterized [11, 28, 29]. Female C57BL/6 mice were used for chemotherapy-induced fatigue experiments, which used 5-FU to induce fatigue, as this strain and sex was used to establish the TFT [30] and in other studies using 5-FU [19, 31].…”

“…This study was limited, however, by its small sample size of eight participants and by its use of TRH, which degrades quickly in the blood [9] and has low oral bioavailability and poor blood-brain barrier penetration, thus requiring parenteral administration of large doses. In contrast, taltirelin (TAL), an analog of TRH, has greater stability than TRH in vivo [10] and a comparable in vitro efficacy [11]. Additionally, it is orally bioavailable and efficacious in rodents [12, 13].…”

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

“…Taltirelin (Ceredist ® , Mitsubishi Tanabe Pharma, Japan, MW 477) exhibits higher stability in the blood and brain compared to TRH, which leads to an increase of 10 -100 fold in its CNS stimulatory action compared to TRH, accompanied by a much longer half-life (t½) [33]. However, taltirelin induces lower thyrotropin (TSH) release in rodents compared to TRH, suggesting a low affinity for receptors in the TSH-secreting cells of the pituitary [34]. Following oral administration to rats and dogs, taltirelin was absorbed through all regions of the small intestine and was detected intact in brain tissue up to 6 h after administration [33].…”

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

“…Changes in fluorescence were detected at the emission wavelength of 515 –575 nm using FLIPR calcium assay kit according to the manufacturer’s recommendation. 34 This kit includes a calcium sensitive dye that is taken into the cytoplasm of the cell during incubation. The kit masking technology remains outside the cell and blocks background fluorescence.…”