title: Neuroprotection by Imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway.
abstract: Depression is accompanied by the activation of the inflammatory-response system, and increased production of proinflammatory cytokines may play a role in the pathophysiology of depressive disorders. Imipramine (IM), a tricyclic antidepressant drug, has recently been shown to promote neurogenesis and improve the survival rate of neurons in the hippocampus. However, whether IM elicits a neuroprotective or anti-inflammatory effect, or promotes the differentiation of neural stem cells (NSCs) remains to be elucidated. In this study, we cultured NSCs derived from the hippocampal tissues of adult rats as an in vitro model to evaluate the NSCs drug-modulation effects of IM. Our results showed that 3 microM IM treatment significantly increased the survival rate of NSCs, and up-regulated the mRNA and protein expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 in Day-7 IM-treated NSCs. Similar to BDNF-treated effect, incubation of NSCs with 3 microM IM increased Bcl-2 protein levels and further prevented lipopolysaccharide (LPS)-induced apoptosis through the activation of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway. Inhibition of BDNF expression with small interfering RNA (siRNA), or blocking the MAPK pathway with U0126 further significantly decreased Bcl-2 protein levels and abrogated the neuroprotective effects of IM against LPS-induced apoptosis in NSCs. In addition, the percentages of serotonin and MAP-2-positive neuronal cells in the Day 7 culture of IM-treated NSCs were significantly increased. By using microdialysis with high performance liquid chromatography-electrochemical detection, the functional release of serotonin in the process of serotoninergic differentiation of IM-treated NSCs was concomitantly increasing and mediated by the activation of the BDNF/MAPK/ERK pathway/Bcl-2 cascades. In sum, the study results indicate that IM can increase the neuroprotective effects, suppress the LPS-induced inflammatory process, and promote serotoninergic differentiation in NSCs via the modulation of the BDNF/MAPK/ERK pathway/Bcl-2 cascades.
authors.affiliation: Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taiwan.
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Peng
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Chen
authors.forename: Yueh-Ching
authors.initials: YC
authors.lastname: Chou
authors.forename: Hung-Hai
authors.initials: HH
authors.lastname: Ku
authors.forename: Cheng-Kuo
authors.initials: CK
authors.lastname: Cheng
authors.forename: Chih-Ju
authors.initials: CJ
authors.lastname: Yen
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Chun-Lan
authors.initials: CL
authors.lastname: Kao
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000166:cytology; D007099:Imipramine / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects*; D013997:Time Factors
chemical_list: D018759:Adrenergic Uptake Inhibitors; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D007099:Imipramine