Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
Biomed Pharmacother. 2024 Oct;179:117399. doi: 10.1016/j.biopha.2024.117399. Epub 2024 Sep 8.
Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.
胎儿的正常发育需要严格控制胎盘中的血清素浓度。这种体内平衡部分由胎盘转运体 OCT3/SLC22A3 维持，该转运体将血清素从胎儿循环中摄取。二甲双胍是一种常用于治疗妊娠糖尿病的抗糖尿病药物，被证明可以抑制 OCT3。因此，我们假设其在怀孕期间的使用可能会破坏胎盘的血清素平衡。本研究使用了三个实验模型系统来验证这一假设：从人足月胎盘分离的原代滋养层细胞、新鲜绒毛状人足月胎盘片段和大鼠足月胎盘灌注。在所有三种模型中都评估了二甲双胍在三个浓度（1µM、10µM 和 100µM）下对血清素转运的抑制作用。用 OCT3 抑制剂地昔帕明（100µM）和帕罗西汀（100µM，一种 SERT 和 OCT3 的双重抑制剂）作为对照。在原代滋养层细胞中，帕罗西汀对血清素摄取的抑制作用最强，其次是地昔帕明。二甲双胍呈浓度依赖性效应，在最高浓度下，血清素摄取减少了多达 57%。在新鲜的绒毛状片段中，其抑制作用不那么明显，但在所有浓度下仍具有统计学意义。在灌注的大鼠胎盘模型中，二甲双胍呈浓度依赖性效应，在最高浓度下，胎盘血清素摄取减少了 44%。我们在所有实验模型中的发现表明，二甲双胍抑制了胎盘 OCT3，导致滋养层摄取的血清素减少。这揭示了可能构成二甲双胍对胎儿发育影响的机制。
