title: Imipramine activates glial cell line-derived neurotrophic factor via early growth response gene 1 in astrocytes.
abstract: Recent evidence has suggested that deficits in glial plasticity contribute to the pathophysiology of depressive disorders. The present study explored early growth response 1 (EGR-1) transcriptional regulation of imipramine-induced glial cell line-derived neurotrophic factor (GDNF) expression in astrocytes. After we observed the induction of GDNF mRNA expression in rat astrocytes in response to imipramine, deletion mutant studies showed that the proximal region between -493 and -114 of the GDNF promoter, which contains three binding sites for EGR-1, was essential for maximal imipramine-induced activation of GDNF promoter. The dose-dependent upregulation of EGR-1 by imipramine, the activation of GDNF by the over-expression of EGR-1 without imipramine and the reduction in the imipramine-induced GDNF mRNA expression after silencing of endogenous EGR-1 demonstrated that EGR-1 is upregulated by imipramine to activate the GDNF promoter. Furthermore, imipramine-induced GDNF mRNA expression was strongly attenuated in primary astrocytes from Egr-1(-/-) mice, and the immunoreactivity to an anti-GDNF antibody in glial fibrillary acidic protein-positive cells was lower in imipramine-treated astrocytes from Egr-1(-/-) mice than in those from Egr-1(+/-) mice. To determine whether mitogen-activated protein kinases (MAPKs) were associated with imipramine-induced EGR-1 expression, we examined the induction of MAPK phosphorylation in response to imipramine. Pretreatment of rat primary astrocytes with the MAPK kinase inhibitor U0126 or the JNK inhibitor SP600125 strongly inhibited imipramine-stimulated EGR-1 expression. In conclusion, we found that imipramine induction of EGR-1 upregulated GDNF in astrocytes in a dose-dependent manner. This upregulation may occur through the MEK/ERK and JNK MAPK pathways, which suggests a new therapeutic mechanism of action for depressive disorders.
authors.affiliation: Department of Adolescent Psychiatry, National Center for Child and Adolescent Psychiatry, Seoul National Hospital, Seoul 143-711, Republic of Korea.
authors.forename: Yeni
authors.initials: Y
authors.lastname: Kim
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Kyooseob
authors.initials: K
authors.lastname: Ha
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000187:drug effects* / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D007099:Imipramine / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000929:Antidepressive Agents, Tricyclic; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D034741:RNA, Small Interfering; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D007099:Imipramine