Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Int J Mol Sci. 2019 Jan 30;20(3):598. doi: 10.3390/ijms20030598.
In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes.
在以前的研究中，我们发现星形胶质细胞对抗氧化应激时诱导抗氧化分子存在区域性差异，这表明星形胶质细胞的区域特异性特征导致神经元的区域特异性易损性。本研究采用中脑神经元与中脑或纹状体星形胶质细胞共培养的方法，用多巴胺能神经毒素 6-羟多巴胺（6-OHDA）作为氧化应激物，研究星形胶质细胞的区域特异性特征。结果发现，6-OHDA 诱导的中脑多巴胺能神经元减少可被星形胶质细胞共培养所抑制。与中脑星形胶质细胞相比，中脑神经元与纹状体星形胶质细胞共培养对 6-OHDA 的抗性更强。此外，来自经 6-OHDA 处理的纹状体星形胶质细胞的条件培养基对 6-OHDA 诱导的神经毒性和氧化应激显示出更强的保护作用，而来自中脑星形胶质细胞的条件培养基则没有。cDNA 微阵列分析显示，中脑和纹状体星形胶质细胞中改变的基因数量均少于任一星形胶质细胞中改变的基因数量。6-OHDA 处理明显上调了纹状体星形胶质细胞中 Nrf2 及其它一些抗氧化或与谷胱甘肽合成和输出有关的 Nrf2 调节的 II 期、III 期解毒分子的表达，但在中脑星形胶质细胞中没有。6-OHDA 诱导的星形胶质细胞基因表达存在明显的区域性差异。这些结果表明，星形胶质细胞对抗氧化应激的保护特征在纹状体星形胶质细胞中更为明显，可能是通过纹状体星形胶质细胞分泌体液因子实现的。
