Riluzole elevates GLT-1 activity and levels in striatal astrocytes.
Riluzole elevates GLT-1 activity and levels in striatal astrocytes.
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DOI：
10.1016/j.neuint.2011.10.017
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发表时间：
2012-01
影响因子：
4.2
通讯作者：
Rattray M
中科院分区：
文献类型：
--
作者：
Carbone M;Duty S;Rattray M
上调星形胶质细胞谷氨酸转运的药物可能是有用的神经保护化合物，通过防止兴奋性毒性。我们建立了一个新的系统来识别通过GLT-1发挥作用的潜在神经保护药物。在生长因子补充剂G5存在下生长的原代小鼠纹状体星形胶质细胞表达高水平的功能性谷氨酸转运蛋白GLT-1（也称为EAAT 2），如通过蛋白质印迹和3 H-谷氨酸摄取测定所评估的，并且在生长因子撤除后水平下降。GLT-1转录增强剂地塞米松（0.1或1 μM）能够防止生长因子停药后GLT-1水平和活性的丧失。与此相反，头孢曲松，一种化合物先前报道，以提高GLT-1的表达，未能调节GLT-1在这个系统中。神经保护化合物利鲁唑（100 μM）通过不依赖于电压敏感性离子通道阻断的机制上调GLT-1水平和活性，因为唑那斯胺（1 mM）不调节GLT-1。最后，CDP-胆碱（10 μM - 1 mM），一种促进GLT-1/EAAT 2与脂筏结合的化合物，在这些条件下不能防止GLT-1丢失。这一观察结果扩展了利鲁唑的已知药理作用，并表明该化合物可能通过星形胶质细胞依赖性机制发挥其神经保护作用。
Drugs which upregulate astrocyte glutamate transport may be useful neuroprotective compounds by preventing excitotoxicity. We set up a new system to identify potential neuroprotective drugs which act through GLT-1. Primary mouse striatal astrocytes grown in the presence of the growth-factor supplement G5 express high levels of the functional glutamate transporter, GLT-1 (also known as EAAT2) as assessed by Western blotting and 3H-glutamate uptake assay, and levels decline following growth factor withdrawal. The GLT-1 transcriptional enhancer dexamethasone (0.1 or 1 μM) was able to prevent loss of GLT-1 levels and activity following growth factor withdrawal. In contrast, ceftriaxone, a compound previously reported to enhance GLT-1 expression, failed to regulate GLT-1 in this system. The neuroprotective compound riluzole (100 μM) upregulated GLT-1 levels and activity, through a mechanism that was not dependent on blockade of voltage-sensitive ion channels, since zonasimide (1 mM) did not regulate GLT-1. Finally, CDP-choline (10 μM – 1 mM), a compound which promotes association of GLT-1/EAAT2 with lipid rafts was unable to prevent GLT-1 loss under these conditions. This observation extends the known pharmacological actions of riluzole, and suggests that this compound may exert its neuroprotective effects through an astrocyte-dependent mechanism.