Neurology Department, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(5):e37331. doi: 10.1371/journal.pone.0037331. Epub 2012 May 14.
Urate is a major antioxidant as well as the enzymatic end product of purine metabolism in humans. Higher levels correlate with a reduced risk of developing Parkinson's disease (PD) and with a slower rate of PD progression. In this study we investigated the effects of modulating intracellular urate concentration on 1-methyl-4-phenyl-pyridinium (MPP(+))-induced degeneration of dopaminergic neurons in cultures of mouse ventral mesencephalon prepared to contain low (neuron-enriched cultures) or high (neuron-glial cultures) percentage of astrocytes. Urate, added to the cultures 24 hours before and during treatment with MPP(+), attenuated the loss of dopaminergic neurons in neuron-enriched cultures and fully prevented their loss and atrophy in neuron-astrocyte cultures. Exogenous urate was found to increase intracellular urate content in cortical neuronal cultures. To assess the effect of reducing cellular urate content on MPP(+)-induced toxicity, mesencephalic neurons were prepared from mice over-expressing urate oxidase (UOx). Transgenic UOx expression decreased endogenous urate content both in neurons and astrocytes. Dopaminergic neurons expressing UOx were more susceptible to MPP(+) in mesencephalic neuron-enriched cultures and to a greater extent in mesencephalic neuron-astrocyte cultures. Our findings correlate intracellular urate content in dopaminergic neurons with their toxin resistance in a cellular model of PD and suggest a facilitative role for astrocytes in the neuroprotective effect of urate.
尿酸是一种重要的抗氧化剂，也是人类嘌呤代谢的酶解终产物。较高的尿酸水平与帕金森病（PD）发病风险降低以及 PD 进展速度减缓相关。在本研究中，我们调查了调节细胞内尿酸浓度对含低（神经元丰富培养物）或高（神经元-神经胶质培养物）百分比星形胶质细胞的小鼠腹侧中脑培养物中 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPP(+)）诱导的多巴胺能神经元变性的影响。在 MPP(+)处理前 24 小时和处理期间将尿酸添加到培养物中，可减轻神经元丰富培养物中多巴胺能神经元的丢失，并完全防止神经元-星形胶质细胞培养物中神经元的丢失和萎缩。发现外源性尿酸可增加皮质神经元培养物中的细胞内尿酸含量。为了评估降低细胞内尿酸含量对 MPP(+)诱导的毒性的影响，从小鼠中制备了尿酸氧化酶（UOx）过度表达的中脑神经元。转基因 UOx 表达降低了神经元和星形胶质细胞中的内源性尿酸含量。在富含中脑神经元的培养物中，表达 UOx 的多巴胺能神经元对 MPP(+)更敏感，在富含中脑神经元-星形胶质细胞的培养物中更为明显。我们的发现将多巴胺能神经元中的细胞内尿酸含量与 PD 细胞模型中的毒素抗性相关联，并表明星形胶质细胞在尿酸的神经保护作用中起促进作用。
