Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain.
Int J Mol Sci. 2024 Aug 23;25(17):9150. doi: 10.3390/ijms25179150.
Sodium tungstate (NaWO) normalizes glucose metabolism in the liver and muscle, activating the Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Because this pathway controls neuronal survival and differentiation, we investigated the effects of NaWO in mouse Neuro2a and human SH-SY5Y neuroblastoma monolayer cell cultures. NaWO promotes differentiation to cholinergic neurites via an increased G1/G0 cell cycle in response to the synergic activation of the Phosphatidylinositol 3-kinase (PI3K/Akt) and ERK1/2 signaling pathways. In Neuro2a cells, NaWO increases protein synthesis by activating the mechanistic target of rapamycin (mTOR) and S6K kinases and GLUT3-mediated glucose uptake, providing the energy and protein synthesis needed for neurite outgrowth. Furthermore, NaWO increased the expression of myocyte enhancer factor 2D (MEF2D), a member of a family of transcription factors involved in neuronal survival and plasticity, through a post-translational mechanism that increases its half-life. Site-directed mutations of residues involved in the sumoylation of the protein abrogated the positive effects of NaWO on the MEF2D-dependent transcriptional activity. In addition, the neuroprotective effects of NaWO were evaluated in the presence of advanced glycation end products (AGEs). AGEs diminished neurite differentiation owing to a reduction in the G1/G0 cell cycle, concomitant with lower expression of MEF2D and the GLUT3 transporter. These negative effects were corrected in both cell lines after incubation with NaWO These findings support the role of NaWO in neuronal plasticity, albeit further experiments using 3D cultures, and animal models will be needed to validate the therapeutic potential of the compound.
钨酸钠（NaWO）可使肝脏和肌肉中的葡萄糖代谢正常化，激活丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路。由于该途径控制神经元的存活和分化，我们研究了 NaWO 在小鼠 Neuro2a 和人 SH-SY5Y 神经母细胞瘤单层细胞培养物中的作用。NaWO 通过协同激活磷脂酰肌醇 3-激酶（PI3K/Akt）和 ERK1/2 信号通路，增加 G1/G0 细胞周期，促进胆碱能神经突的分化。在 Neuro2a 细胞中，NaWO 通过激活雷帕霉素（mTOR）和 S6K 激酶以及 GLUT3 介导的葡萄糖摄取来增加蛋白质合成，为神经突生长提供所需的能量和蛋白质合成。此外，NaWO 通过增加其半衰期的翻译后机制增加肌细胞增强因子 2D（MEF2D）的表达，MEF2D 是一种参与神经元存活和可塑性的转录因子家族的成员。涉及该蛋白 sumoylation 的残基的定点突变会破坏 NaWO 对 MEF2D 依赖性转录活性的积极影响。此外，还在存在晚期糖基化终产物（AGEs）的情况下评估了 NaWO 的神经保护作用。AGEs 由于 G1/G0 细胞周期减少，同时 MEF2D 和 GLUT3 转运蛋白的表达降低，从而减弱了神经突分化。在用 NaWO 孵育后，这两种细胞系中的这些负效应都得到了纠正。这些发现支持了 NaWO 在神经元可塑性中的作用，尽管需要使用 3D 培养物和动物模型进行进一步实验，以验证该化合物的治疗潜力。
