Chronic inhibitory effect of riluzole on trophic factor production.
Chronic inhibitory effect of riluzole on trophic factor production.
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DOI：
10.1016/j.expneurol.2015.05.016
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发表时间：
2015-09
影响因子：
5.3
通讯作者：
Estevez AG
中科院分区：
文献类型：
--
作者：
Dennys CN;Armstrong J;Levy M;Byun YJ;Ramdial KR;Bott M;Rossi FH;Fernández-Valle C;Franco MC;Estevez AG
阿曲唑是FDA批准的唯一用于治疗肌萎缩侧索硬化症（ALS）的药物。然而，这种药物对ALS患者提供了适度的保护，通过一种仍有争议的机制延长了几个月的生命。在利鲁唑的存在下，星形胶质细胞增加运动神经元保护因子的产生。利鲁唑对ALS的保护作用可能与其刺激运动神经元相关细胞产生营养因子有关。在这里，我们研究了条件培养基的星形胶质细胞和雪旺细胞急性或慢性孵育利鲁唑对营养因子剥夺运动神经元存活的影响。虽然急性利鲁唑孵育诱导星形胶质细胞和雪旺细胞分泌CT-1，慢性治疗刺激营养因子的生产显着减少相比，未经处理的文化。因此，利鲁唑急性处理的星形胶质细胞和雪旺细胞的条件培养基保护运动神经元免于营养因子剥夺诱导的细胞死亡。通过与CT-1中和抗体孵育来防止运动神经元保护。相比之下，长期用利鲁唑处理的星形胶质细胞和雪旺细胞的条件培养基没有保护作用。利鲁唑对小鼠的急性和慢性治疗对脊髓、坐骨神经和大脑中营养因子的产生相反的影响。在利鲁唑治疗的第一天，脊髓中CT-1和GDNF以及坐骨神经中CT-1的产生增加，但在长期治疗后水平显著下降。在脑中观察到CT-1和BDNF的类似结果，而利鲁唑治疗后GDNF水平没有变化。我们的研究结果表明，利鲁唑调节涉及蛋白质合成的持久过程，这可能与利鲁唑的治疗效果有关。改变利鲁唑给药方案，通过不连续的长期治疗，有利于药物对营养因子产生的急性作用，可能会改善ALS患者治疗的结局。
Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). However, the drug affords moderate protection to ALS patients, extending life for a few months by a mechanism that remains controversial. In the presence of riluzole, astrocytes increase the production of factors protective to motor neurons. The stimulation of trophic factor production by motor neuron associated cells may contribute to riluzole’s protective effect in ALS. Here, we investigated the effects of media conditioned by astrocytes and Schwann cells acutely or chronically incubated with riluzole on trophic factor-deprived motor neuron survival. While acute riluzole incubation induced CT-1 secretion by astrocytes and Schwann cells, chronic treatment stimulated a significant decrease in trophic factor production compared to untreated cultures. Accordingly, conditioned media from astrocytes and Schwann cells acutely treated with riluzole protected motor neurons from trophic factor deprivation-induced cell death. Motor neuron protection was prevented by incubation with CT-1 neutralizing antibodies. In contrast, conditioned media from astrocytes and Schwann cells chronically treated with riluzole was not protective. Acute and chronic treatment of mice with riluzole showed opposite effects on trophic factor production in spinal cord, sciatic nerve and brain. There was an increase in the production of CT-1 and GDNF in the spinal cord and CT-1 in the sciatic nerve during the first days of treatment with riluzole, but the levels dropped significantly after chronic treatment with the drug. Similar results were observed in brain for CT-1 and BDNF while there was no change in GDNF levels after riluzole treatment. Our results reveal that riluzole regulates long-lasting processes involving protein synthesis, which may be relevant for riluzole therapeutic effects. Changing the regimen of riluzole administration to favor the acute effect of the drug on trophic factor production by discontinuous long-term treatment may improve the outcome of ALS patient therapy.