Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health and Science University, Portland, Oregon.
Department of Neurology, Oregon Health and Science University, Portland, Oregon.
Endocrinology. 2018 Jul 1;159(7):2733-2740. doi: 10.1210/en.2018-00065.
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.
甲状腺刺激剂是一类可刺激组织选择性甲状腺激素作用的实验药物。因此，甲状腺刺激剂应该对下丘脑-垂体-甲状腺轴（HPT）有影响，但迄今为止，尚未有关于其作用的详细信息及其对全身甲状腺激素水平的后续影响的报道。在这里，我们比较了研究充分的甲状腺刺激剂索贝替尔莫和新开发的索贝替尔莫前药 Sob-AM2 对 HPT 轴的影响，该前药将索贝替尔莫靶向到中枢神经系统（CNS）。与内源性甲状腺激素相似，索贝替尔莫和 Sob-AM2 的给药以与其特定的组织分布特性（分别为外周与中枢神经系统）相关的方式抑制 HPT 轴基因转录水平。以≥10μg/kg/d 的浓度给雄性 C57BL/6 小鼠连续 29 天给予索贝替尔莫和 Sob-AM2，可诱导类似于中枢性甲状腺功能减退的状态，其特征为循环 T4 和 T3 耗尽和 TSH 水平正常。然而，尽管存在全身性 T4 和 T3 耗竭，索贝替尔莫和 Sob-AM2 处理的小鼠没有出现甲状腺功能减退的迹象，这可能是由于甲状腺激素耗竭背景中存在甲状腺刺激剂。
