Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release.
Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release.
复制标题
尿酸盐的神经保护作用是通过增强星形胶质细胞谷胱甘肽的合成和释放来介导的
DOI：
10.1016/j.nbd.2015.08.022
复制
发表时间：
2015-10
影响因子：
6.1
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
--
作者：
Bakshi R;Zhang H;Logan R;Joshi I;Xu Y;Chen X;Schwarzschild MA
基于流行病学观察、临床前模型和多种神经系统疾病（包括帕金森病（PD））的早期临床试验结果，尿酸盐已成为一种有前途的神经保护靶点。本研究探讨尿酸盐神经保护作用的星形胶质细胞机制。从尿酸盐与车辆处理的星形胶质细胞的条件培养基的有针对性的生化筛选确定显着升高的谷胱甘肽（GSH）浓度作为尿酸盐的星形胶质细胞依赖性神经保护作用的候选介质。尿酸盐处理还诱导核因子（红细胞衍生2）样2（Nrf2）蛋白的核转位及其主要靶基因在原代星形胶质细胞培养物中的转录激活。当GSH在条件培养基中被耗尽时，尿酸盐的神经保护作用通过靶向其合成或由星形胶质细胞释放而减弱。总之，这些结果暗示GSH作为细胞外星形胶质细胞因子介导尿酸盐在PD细胞模型中的保护作用。这些结果还表明，尿酸盐可以通过诱导Nrf2信号通路（星形胶质细胞中氧化应激反应的主要调节因子），采用一种新的间接神经保护机制。
Urate has emerged as a promising target for neuroprotection based on epidemiological observations, preclinical models, and early clinical trial results in multiple neurologic diseases, including Parkinson's disease (PD). This study investigates the astrocytic mechanism of urate's neuroprotective effect. Targeted biochemical screens of conditioned medium from urate- versus vehicle-treated astrocytes identified markedly elevated glutathione (GSH) concentrations as a candidate mediator of urate's astrocyte-dependent neuroprotective effects. Urate treatment also induced the nuclear translocation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein and transcriptional activation of its key target genes in primary astrocytic cultures. Urate's neuroprotective effect was attenuated when GSH was depleted in the conditioned media either by targeting its synthesis or release by astrocytes. Overall, these results implicate GSH as the extracellular astrocytic factor mediating the protective effect of urate in a cellular model of PD. These results also show that urate can employ a novel indirect neuroprotective mechanism via induction of the Nrf2 signaling pathway, a master regulator of the response to oxidative stress, in astrocytes.