Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity.
Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity.
复制标题
促红细胞生成素诱导的神经保护需要胱氨酸谷氨酸交换活性。
DOI：
10.1016/j.brainres.2010.01.040
复制
发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Sontheimer,Harald
中科院分区：
文献类型：
--
作者：
Sims,Brian;Clarke,Melinda;Njah,Wilfred;Hopkins,E'lanaShuford;Sontheimer,Harald
促红细胞生成素(EPO)多年来一直用于新生儿治疗早产儿贫血。EPO也被建议用于治疗新生儿脑损伤，因为越来越多的证据表明EPO具有神经保护作用。然而，促红细胞生成素的神经保护作用机制却知之甚少。在这项研究中，我们假设EPO可能通过增强细胞谷胱甘肽(GSH)带来的细胞氧化还原防御来提供神经保护。这在分化的皮质神经干细胞的培养中进行了检验，并使用B104细胞系作为模型系统。我们的数据显示，促红细胞生成素引起XC−系统的表达和活性随时间和剂量的增加而增加，XC DNA是负责摄取半胱氨酸以产生谷胱甘肽的转运体。在分化的神经干细胞和经EPO处理的B104细胞中，胱氨酸摄取量增加3-5倍。细胞暴露于100μ的M红藻氨酸可抑制细胞的谷胱甘肽并引起兴奋性毒性，但在红藻氨酸持续存在的情况下，促红细胞生成素可完全恢复细胞的谷胱甘肽水平和细胞活力。如果在促红细胞生成素存在的情况下使用S4-CpG从药理上抑制XC−系统，导致B104细胞和培养的小鼠皮质神经干细胞显著死亡，则促红细胞生成素的这种拯救作用消失。这也可以用XCT siRNA来降低XCT的表达。提示促红细胞生成素对XC系统−活性和蛋白表达有正向调节作用，直接解释了其神经保护作用。
Erythropoietin (Epo) has been used for many years in neonates for the treatment of anemia of prematurity. Epo has also been proposed for treatment of neonatal brain injury, as mounting evidence suggests neuroprotective properties for Epo. However, Epo's neuroprotective mechanism of action is poorly understood. In this study we hypothesized that Epo may confer neuroprotection by enhancing cellular redox defense brought about by cellular glutathione (GSH). This was examined in cultures of differentiated cortical neural stem cells and using the B104 cell line as model systems. Our data shows that Epo causes a time- and dose-dependent increase in expression and activity of system Xc−, the transporter responsible for uptake of cystine for the production of glutathione. Cystine uptake increases 3–5 fold in differentiated neural stem cells and B104 cells treated with Epo. Exposure of cells to 100μM kainate suppressed cellular GSH and caused excitotoxicity, but GSH levels and cell viability were completely restored by Epo in the continued presence of kainate. This rescue effect of Epo vanished if system Xc−was inhibited pharmacologically using S4-CPG in the presence of Epo leading to marked cell death of B104 cells and cultured mouse cortical neural stem cells. This could also be achieved using xCT siRNA to decrease xCT expression. This data suggests that system Xc−activity and protein expression are positively regulated by Epo directly explaining its neuroprotective effect.