Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama, Kure, Japan.
Brain Res. 2011 Apr 12;1384:1-8. doi: 10.1016/j.brainres.2011.01.100. Epub 2011 Feb 3.
Riluzole is approved for the treatment of amyotrophic lateral sclerosis (ALS); however, recent accumulating evidence suggests that riluzole is also effective for the treatment of psychiatric disorders, such as mood disorders. Plastic change in the brain induced by neurotrophic factors/growth factors is thought to be involved in the mechanism of antidepressants. This study investigated the mechanism of riluzole-induced glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells), a model of astrocytes. The study investigated the phosphorylation of cAMP response element binding protein (CREB), an important transcriptional factor of the gdnf gene, and found that riluzole increased CREB phosphorylation in a time-dependent manner, peaking at 40min after treatment. The riluzole-induced CREB phosphorylation was completely blocked by a mitogen-activated protein kinase kinase (MEK) inhibitor (U0126). Riluzole increased extracellular signal-regulated kinase (ERK) activation prior to CREB phosphorylation. These results suggest that riluzole rapidly activates the MEK/ERK/CREB pathway. Furthermore, two types of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (SU5402 and PD173074) completely blocked riluzole-induced CREB phosphorylation. In addition, riluzole rapidly phosphorylated FGFR substrate 2α (FRS2α), a major adaptor protein of FGFR. These findings suggest that riluzole induces CREB phosphorylation through FGFR. In addition, PD173074 inhibited riluzole-induced GDNF production. In contrast, l-glutamate and a glutamate transporter inhibitor (t-PDC) did not yield any effects in either CREB phosphorylation or GDNF production. These findings suggest that riluzole rapidly activates a MEK/ERK/CREB pathway through FGFR in a glutamate transporter-independent manner, followed by GDNF expression in C6 cells.
利鲁唑获批用于治疗肌萎缩侧索硬化症（ALS）；然而，最近越来越多的证据表明，利鲁唑对治疗精神障碍也有效，如情绪障碍。神经营养因子/生长因子诱导的大脑可塑性被认为与抗抑郁药的作用机制有关。本研究旨在探讨利鲁唑诱导大鼠 C6 神经胶质瘤细胞（C6 细胞）星形胶质细胞衍生神经营养因子（GDNF）产生的机制。该研究检测了 cAMP 反应元件结合蛋白（CREB）的磷酸化，CREB 是 gdnf 基因的一个重要转录因子，结果发现利鲁唑能时间依赖性地增加 CREB 的磷酸化，在处理 40min 时达到高峰。丝裂原活化蛋白激酶激酶（MEK）抑制剂（U0126）完全阻断了利鲁唑诱导的 CREB 磷酸化。利鲁唑在 CREB 磷酸化之前激活细胞外信号调节激酶（ERK）。这些结果表明利鲁唑能快速激活 MEK/ERK/CREB 通路。此外，两种成纤维细胞生长因子受体（FGFR）酪氨酸激酶抑制剂（SU5402 和 PD173074）完全阻断了利鲁唑诱导的 CREB 磷酸化。此外，利鲁唑还能快速磷酸化 FGFR 底物 2α（FRS2α），这是 FGFR 的主要衔接蛋白。这些发现表明利鲁唑通过 FGFR 诱导 CREB 磷酸化。此外，PD173074 抑制了利鲁唑诱导的 GDNF 产生。相比之下，l-谷氨酸和谷氨酸转运体抑制剂（t-PDC）在 CREB 磷酸化或 GDNF 产生方面均无任何作用。这些发现表明，利鲁唑通过 FGFR 以谷氨酸转运体非依赖性方式快速激活 MEK/ERK/CREB 通路，继而在 C6 细胞中表达 GDNF。
