Hanyang Biomedical Research Institute, Hanyang University, Seoul, 04763, Korea.
Paean Biotechnology, Inc., Daejeon, 34028, Korea.
Sci Rep. 2019 Sep 20;9(1):13659. doi: 10.1038/s41598-019-49876-6.
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive movement disturbances caused by the selective loss of dopamine (DA) neurons in the substantia nigra. Despite the identification of the causal mechanisms underlying the pathogenesis of PD, effective treatments remain elusive. In this study, we observed that a low level of fetal bovine serum (FBS) effectively induced DA neurons in rat neural precursor cells (NPCs) by enhancing nuclear receptor-related 1 protein (NURR1) expression. Among the various components of FBS, the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were identified as key factors for the induction of DA neurons. Since an overdose of thyroid hormones can cause hyperthyroidism, we synthesized several thyroid hormone derivatives that can partially activate thyroid hormone receptors and induce the complete differentiation of NPCs into DA neurons. Two derivatives (#3 and #9) showed positive effects on the induction and maturation of DA neurons without showing significant affinity for the thyroid hormone receptor. They also effectively protected and restored DA neurons from neurotoxic insults. Taken together, these observations demonstrate that thyroid hormone derivatives can strongly induce DA neuron differentiation while avoiding excessive thyroid stimulation and might therefore be useful candidates for PD treatment.
帕金森病（PD）是一种神经退行性疾病，其特征是由于黑质中多巴胺（DA）神经元的选择性丧失而导致进行性运动障碍。尽管已经确定了 PD 发病机制的因果机制，但仍难以找到有效的治疗方法。在这项研究中，我们观察到低胎牛血清（FBS）水平通过增强核受体相关 1 蛋白（NURR1）的表达，有效地诱导大鼠神经前体细胞（NPC）中的 DA 神经元。在 FBS 的各种成分中，甲状腺激素三碘甲状腺原氨酸（T3）和甲状腺素（T4）被鉴定为诱导 DA 神经元的关键因素。由于甲状腺激素过量会导致甲状腺功能亢进，因此我们合成了几种可以部分激活甲状腺激素受体并诱导 NPC 完全分化为 DA 神经元的甲状腺激素衍生物。两种衍生物（#3 和 #9）对 DA 神经元的诱导和成熟具有积极作用，而对甲状腺激素受体没有明显亲和力。它们还能有效保护和恢复 DA 神经元免受神经毒性损伤。总之，这些观察结果表明，甲状腺激素衍生物可以强烈诱导 DA 神经元分化，同时避免过度的甲状腺刺激，因此可能是 PD 治疗的有用候选药物。
