Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA.
J Neurochem. 2012 Oct;123(1):172-81. doi: 10.1111/j.1471-4159.2012.07820.x. Epub 2012 Aug 22.
Urate is the end product of purine metabolism and a major antioxidant circulating in humans. Recent data link higher levels of urate with a reduced risk of developing Parkinson's disease and with a slower rate of its progression. In this study, we investigated the role of astrocytes in urate-induced protection of dopaminergic cells in a cellular model of Parkinson's disease. In mixed cultures of dopaminergic cells and astrocytes oxidative stress-induced cell death and protein damage were reduced by urate. By contrast, urate was not protective in pure dopaminergic cell cultures. Physical contact between dopaminergic cells and astrocytes was not required for astrocyte-dependent rescue as shown by conditioned medium experiments. Urate accumulation in dopaminergic cells and astrocytes was blocked by pharmacological inhibitors of urate transporters expressed differentially in these cells. The ability of a urate transport blocker to prevent urate accumulation into astroglial (but not dopaminergic) cells predicted its ability to prevent dopaminergic cell death. Transgenic expression of uricase reduced urate accumulation in astrocytes and attenuated the protective influence of urate on dopaminergic cells. These data indicate that urate might act within astrocytes to trigger release of molecule(s) that are protective for dopaminergic cells.
尿酸是嘌呤代谢的终产物，也是人类循环中的主要抗氧化剂。最近的数据表明，尿酸水平较高与帕金森病发病风险降低和疾病进展速度减缓有关。在这项研究中，我们研究了星形胶质细胞在帕金森病细胞模型中尿酸诱导的多巴胺能细胞保护中的作用。在多巴胺能细胞和星形胶质细胞的混合培养物中，尿酸可减少氧化应激诱导的细胞死亡和蛋白质损伤。相比之下，尿酸在纯多巴胺能细胞培养物中没有保护作用。条件培养基实验表明，多巴胺能细胞和星形胶质细胞之间不需要物理接触即可实现星形胶质细胞依赖性拯救。尿酸转运体在这些细胞中差异表达，尿酸转运体的药理学抑制剂可阻断多巴胺能细胞和星形胶质细胞中的尿酸积累。尿酸转运体阻滞剂防止尿酸积累到星形胶质细胞（而非多巴胺能细胞）的能力可预测其阻止多巴胺能细胞死亡的能力。尿酸酶的转基因表达可减少星形胶质细胞中的尿酸积累，并减弱尿酸对多巴胺能细胞的保护作用。这些数据表明，尿酸可能在星形胶质细胞内发挥作用，触发对多巴胺能细胞具有保护作用的分子（s）的释放。
