Baldassarro Vito Antonio, Quadalti Corinne, Runfola Massimiliano, Manera Clementina, Rapposelli Simona, Calzà Laura
Department of Veterinary Medical Science (DIMEVET), University of Bologna, 40064 Bologna, Italy.
Department of Pharmacy and Biotechnology (FaBit), University of Bologna, 40126 Bologna, Italy.
Pharmaceuticals (Basel). 2023 Aug 25;16(9):1207. doi: 10.3390/ph16091207.
Oligodendrocytes and their precursors are the cells responsible for developmental myelination and myelin repair during adulthood. Their differentiation and maturation processes are regulated by a complex molecular machinery driven mainly by triiodothyronine (T3), the genomic active form of thyroid hormone, which binds to thyroid hormone receptors (TRs), regulating the expression of target genes. Different molecular tools have been developed to mimic T3 action in an attempt to overcome the myelin repair deficit that underlies various central nervous system pathologies. In this study, we used a well-established in vitro model of neural stem cell-derived oligodendrocyte precursor cells (OPCs) to test the effects of two compounds: the TRβ1 ligand IS25 and its pro-drug TG68. We showed that treatment with TG68 induces OPC differentiation/maturation as well as both the natural ligand and the best-known TRβ1 synthetic ligand, GC-1. We then described that, unlike T3, TG68 can fully overcome the cytokine-mediated oligodendrocyte differentiation block. In conclusion, we showed the ability of a new synthetic compound to stimulate OPC differentiation and overcome inflammation-mediated pathological conditions. Further studies will clarify whether the compound acts as a pro-drug to produce the TRβ1 ligand IS25 or if its action is mediated by secondary mechanisms such as AMPK activation.
少突胶质细胞及其前体细胞是负责成年期发育性髓鞘形成和髓鞘修复的细胞。它们的分化和成熟过程由一个复杂的分子机制调控，该机制主要由三碘甲状腺原氨酸（T3）驱动，T3是甲状腺激素的基因组活性形式，它与甲状腺激素受体（TRs）结合，调节靶基因的表达。已经开发出不同的分子工具来模拟T3的作用，试图克服作为各种中枢神经系统疾病基础的髓鞘修复缺陷。在本研究中，我们使用了一个成熟的神经干细胞衍生的少突胶质细胞前体细胞（OPCs）体外模型来测试两种化合物的作用：TRβ1配体IS25及其前体药物TG68。我们发现，用TG68处理可诱导OPC分化/成熟，天然配体和最著名的TRβ1合成配体GC-1也有同样效果。然后我们描述了，与T3不同，TG68可以完全克服细胞因子介导的少突胶质细胞分化阻滞。总之，我们展示了一种新的合成化合物刺激OPC分化并克服炎症介导的病理状况的能力。进一步的研究将阐明该化合物是否作为前体药物产生TRβ1配体IS25，或者其作用是否由诸如AMPK激活等二级机制介导。
