title: Riluzole-induced glial cell line-derived neurotrophic factor production is regulated through fibroblast growth factor receptor signaling in rat C6 glioma cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mami
authors.initials: M
authors.lastname: Tsuchioka
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka
authors.forename: Ryoya
authors.initials: R
authors.lastname: Yano
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shibasaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Kajiatani
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000473:pathology; D018698:Glutamic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D018698:Glutamic Acid; D019782:Riluzole; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat