Dennys Cassandra N, Armstrong JeNay, Levy Mark, Byun Youn Jung, Ramdial Kristina R, Bott Marga, Rossi Fabian H, Fernández-Valle Cristina, Franco Maria Clara, Estevez Alvaro G
Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
Orlando Veteran Administration Healthcare System, Orlando, FL 32803, United States.
Exp Neurol. 2015 Sep;271:301-7. doi: 10.1016/j.expneurol.2015.05.016. Epub 2015 Jun 10.
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.
利鲁唑是美国食品药品监督管理局（FDA）批准的唯一用于治疗肌萎缩侧索硬化症（ALS）的药物。然而，该药物对ALS患者的保护作用有限，通过一种仍存在争议的机制使患者寿命延长几个月。在有利鲁唑存在的情况下，星形胶质细胞会增加对运动神经元有保护作用的因子的产生。运动神经元相关细胞对营养因子产生的刺激可能有助于利鲁唑在ALS中的保护作用。在此，我们研究了用利鲁唑急性或慢性孵育的星形胶质细胞和雪旺氏细胞所产生的条件培养基对缺乏营养因子的运动神经元存活的影响。虽然利鲁唑急性孵育可诱导星形胶质细胞和雪旺氏细胞分泌CT-1，但与未处理的培养物相比，慢性处理会刺激营养因子产生显著减少。因此，用利鲁唑急性处理的星形胶质细胞和雪旺氏细胞的条件培养基可保护运动神经元免受营养因子剥夺诱导的细胞死亡。用CT-1中和抗体孵育可阻止运动神经元的保护作用。相比之下，用利鲁唑慢性处理的星形胶质细胞和雪旺氏细胞的条件培养基没有保护作用。利鲁唑对小鼠进行急性和慢性处理对脊髓、坐骨神经和大脑中的营养因子产生显示出相反的作用。在利鲁唑治疗的最初几天，脊髓中CT-1和GDNF的产生增加，坐骨神经中CT-1的产生增加，但在该药物慢性处理后这些水平显著下降。在大脑中观察到CT-1和BDNF有类似结果，而利鲁唑治疗后GDNF水平没有变化。我们的结果表明，利鲁唑调节涉及蛋白质合成的长期过程，这可能与利鲁唑的治疗效果相关。通过间断长期治疗改变利鲁唑给药方案以利于药物对营养因子产生的急性作用，可能会改善ALS患者的治疗结果。
