Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Section of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Biomolecules. 2024 Jul 15;14(7):856. doi: 10.3390/biom14070856.
The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson's disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake.
胰岛素对二价金属转运蛋白-1（DMT1）的调节作用先前已在胰岛细胞中描述过，在急性缺血性脑卒中患者和帕金森病 6-羟多巴胺（6-OHDA）大鼠模型的实验性脑缺血中，发现胰岛素和胰岛素样生长因子 1 治疗具有显著的神经保护作用，在该模型中描述了 DMT1 的作用。根据 DMT1 的调节作用，先前在缺血性神经退行性变的早期阶段（即体外和体内）被描述为 NF-kB 的靶基因，并且胰岛素通过控制 NFkB 信号转导来保护大鼠心肌细胞免于缺血性细胞死亡，我们评估了胰岛素在缺血性神经退行性变过程中与 DMT1 表达和功能的关系。 在分化的人神经母细胞瘤细胞 SK-N-SH 和原代培养的小鼠皮质神经元中，评估胰岛素的神经保护作用，这些细胞分别在氧葡萄糖剥夺（OGD） 8 小时或 3 小时条件下，用或不用 300 nM 胰岛素处理。在这两种细胞模型中，根据细胞死亡来评估胰岛素在 OGD 中的神经保护作用，在 SK-N-SH 中评估 DMT1 蛋白表达和急性亚铁处理，在酸性条件下进行亚铁处理，已知这种条件能促进作为质子共转运体的 DMT1 的最大摄取；并分析了原代培养的小鼠皮质神经元中已经对 NF-kB 有反应的 1B/DMT1 小鼠启动子的转激活。 在 OGD 期间，胰岛素的神经保护作用与 DMT1 蛋白表达和 1B/DMT1 小鼠启动子转激活的下调同时发生。我们还显示了在急性亚铁处理后，胰岛素依赖的细胞死亡保护作用。 总之，尽管这只是初步的评估，但它突出了 DMT1 作为可能的药理学靶标的特殊作用，在体外神经元缺血和急性亚铁摄取期间，胰岛素通过 DMT1 发挥神经保护作用。
