Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Biochem Pharmacol. 2014 Apr 1;88(3):384-92. doi: 10.1016/j.bcp.2014.02.001. Epub 2014 Feb 15.
The brain is especially sensitive to oxidative stress due to its high rate of oxidative metabolism, relatively low levels of antioxidant enzymes, and high concentrations of Fe/Cu ions. During the neurodegeneration process, the aggregation of proteins Aβ, accompanies oxidative stress. We explored the potential of thiophosphate derivatives to rescue neurons from oxidative stress and Aβ toxicity. We evaluated the neuroprotective effect of ATP-γ-S, ADP-β-S, and GDP-β-S on primary cortical neuronal cells exposed to several insults, including treatment with FeSO4, co-application of H2O2 and FeSO4, and addition of Aβ42. Upon treatment with FeSO4, phosphorothioate analogues exhibited up to 3000-fold better neuroprotectant activity than the corresponding parent nucleotides. Likewise, phosphorothioate analogues proved to be up to 30-fold better neuroprotectants than the corresponding parent nucleotides upon treatment with both H2O2 and FeSO4. When we exposed primary neuron and astrocyte cultures to 50 μM Aβ42-induced cell death, we found that ATP-γ-S significantly improved cell morphology and maintained culture viability with an IC50 value of 0.8 μM. Finally, we evaluated the viability of neuroblastoma cells under hypoxic conditions in the presence of ATP-γ-S and found that the latter was involved in the regulation of HIF-1a and stabilized mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), which promote cell survival and proliferation. Based on its high potency as a neuroprotectant, we propose ATP-γ-S as a highly promising, biocompatible, and water-soluble drug candidate for the treatment of neurodegenerative disorders.
大脑由于其高氧化代谢率、相对较低的抗氧化酶水平和高浓度的 Fe/Cu 离子，特别容易受到氧化应激的影响。在神经退行性过程中，蛋白质 Aβ 的聚集伴随着氧化应激。我们探索了硫代膦酸酯衍生物在保护神经元免受氧化应激和 Aβ 毒性方面的潜力。我们评估了 ATP-γ-S、ADP-β-S 和 GDP-β-S 对暴露于几种损伤的原代皮质神经元细胞的神经保护作用，包括用 FeSO4 处理、同时应用 H2O2 和 FeSO4 以及添加 Aβ42。在用 FeSO4 处理时，硫代磷酸酯类似物的神经保护活性比相应的母体核苷酸高 3000 倍。同样，在用 H2O2 和 FeSO4 处理时，硫代磷酸酯类似物的神经保护活性比相应的母体核苷酸高 30 倍。当我们将原代神经元和星形胶质细胞培养物暴露于 50 μM Aβ42 诱导的细胞死亡时，我们发现 ATP-γ-S 显著改善了细胞形态并维持了培养物的活力，IC50 值为 0.8 μM。最后，我们在存在 ATP-γ-S 的情况下评估了缺氧条件下神经母细胞瘤细胞的活力，发现后者参与了 HIF-1a 的调节，并稳定了血管内皮生长因子 (VEGF) 和葡萄糖转运蛋白 1 (GLUT-1) 的 mRNA 水平，这有助于细胞的存活和增殖。基于其作为神经保护剂的高效性，我们提出 ATP-γ-S 是一种很有前途的、生物相容的、水溶性药物候选物，可用于治疗神经退行性疾病。
