Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics - PubMed (original) (raw)

Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics

Skylar J Ferrara et al. Endocrinology. 2018.

Abstract

Thyromimetics represent a class of experimental drugs that can stimulate tissue-selective thyroid hormone action. As such, thyromimetics should have effects on the hypothalamic-pituitary-thyroid (HPT) axis, but details of this action and the subsequent effects on systemic thyroid hormone levels have not been reported to date. Here, we compare the HPT-axis effects of sobetirome, a well-studied thyromimetic, with Sob-AM2, a newly developed prodrug of sobetirome that targets sobetirome distribution to the central nervous system (CNS). Similar to endogenous thyroid hormone, administration of sobetirome and Sob-AM2 suppress HPT-axis gene transcript levels in a manner that correlates to their specific tissue distribution properties (periphery vs CNS, respectively). Dosing male C57BL/6 mice with sobetirome and Sob-AM2 at concentrations ≥10 μg/kg/d for 29 days induces a state similar to central hypothyroidism characterized by depleted circulating T4 and T3 and normal TSH levels. However, despite the systemic T4 and T3 depletion, the sobetirome- and Sob-AM2-treated mice do not show signs of hypothyroidism, which may result from the presence of the thyromimetic in the thyroid hormone-depleted background.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

HPT axis diagram with major feedback loops and the drug molecules used in this study. TH, thyroid hormone.

Figure 2.

Figure 2.

Quantitative PCR dose-response curves for axis gene suppression at 6 h following administration of T3, sobetirome, or Sob-AM2. Samples were run in duplicate with n = 5 per dose per compound. All data points represent mean ± SEM.

Figure 3.

Figure 3.

(A, B) Total T4, (C) total T3, and (D) TSH measurements in systemic circulation after chronic treatment with Sob and Sob-AM2 IP for 29 d (n = 4 per group). (D) Hyperthyroid mice (n = 5) were given 1 mg/kg T3 daily for 5 d; hypothyroid mice (n = 5) were administered methimazole and perchlorate water for 2 wk. All data represent mean ± SEM. Statistical analyses were performed using the two-tailed Student t test comparing individual groups with the appropriate vehicle group or as noted. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. ns, not significant; sob, sobetirome.

Figure 4.

Figure 4.

(A) Differences in body weight between age-matched hypothyroid and euthyroid mice. (B–D) Heart and body weight comparisons after chronic IP dosing with sobetirome and Sob-AM2 for 29 d. All data represent mean ± SEM. Statistical analyses were performed using the two-tailed Student t test comparing individual groups with the appropriate vehicle group or as noted. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.

References

    1. Fekete C, Lechan RM. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev. 2014;35(2):159–194. - PMC - PubMed
    1. Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol. 2014;171(5):R197–R208. - PubMed
    1. Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007;37(1-2):11–53. - PubMed
    1. Medici M, Visser WE, Visser TJ, Peeters RP. Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand? Endocr Rev. 2015;36(2):214–244. - PubMed
    1. Bernal J, Guadaño-Ferraz A, Morte B. Thyroid hormone transporters-functions and clinical implications [published corrections appear in Nat Rev Endocrinol. 2015;11:506 and 2015;11:690] Nat Rev Endocrinol. 2015;11(12):406–417. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources