PMID- 17566715 OWN - NLM STAT- MEDLINE DCOM- 20080418 LR - 20131121 IS - 0924-977X (Print) IS - 0924-977X (Linking) VI - 18 IP - 2 DP - 2008 Feb TI - Neuroprotection by Imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway. PG - 128-40 AB - 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. FAU - Peng, Chi-Hsien AU - Peng CH AD - Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taiwan. FAU - Chiou, Shih-Hwa AU - Chiou SH FAU - Chen, Shih-Jen AU - Chen SJ FAU - Chou, Yueh-Ching AU - Chou YC FAU - Ku, Hung-Hai AU - Ku HH FAU - Cheng, Cheng-Kuo AU - Cheng CK FAU - Yen, Chih-Ju AU - Yen CJ FAU - Tsai, Tung-Hu AU - Tsai TH FAU - Chang, Yuh-Lih AU - Chang YL FAU - Kao, Chun-Lan AU - Kao CL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070612 PL - Netherlands TA - Eur Neuropsychopharmacol JT - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology JID - 9111390 RN - 0 (Adrenergic Uptake Inhibitors) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (Lipopolysaccharides) RN - 0 (Nerve Tissue Proteins) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - OGG85SX4E4 (Imipramine) SB - IM MH - Adrenergic Uptake Inhibitors/*pharmacology MH - Analysis of Variance MH - Animals MH - Apoptosis/*drug effects MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Differentiation/drug effects MH - Cell Survival/drug effects MH - Cells, Cultured MH - Enzyme Inhibitors/pharmacology MH - Enzyme-Linked Immunosorbent Assay MH - Hippocampus/cytology MH - Imipramine/*pharmacology MH - In Situ Nick-End Labeling MH - Lipopolysaccharides/pharmacology MH - Mitogen-Activated Protein Kinase Kinases/*metabolism MH - Nerve Tissue Proteins/metabolism MH - Neurons/*drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/*drug effects MH - Stem Cells/*drug effects MH - Time Factors EDAT- 2007/06/15 09:00 MHDA- 2008/04/19 09:00 CRDT- 2007/06/15 09:00 PHST- 2006/10/11 00:00 [received] PHST- 2007/04/15 00:00 [revised] PHST- 2007/05/07 00:00 [accepted] PHST- 2007/06/15 09:00 [pubmed] PHST- 2008/04/19 09:00 [medline] PHST- 2007/06/15 09:00 [entrez] AID - S0924-977X(07)00101-0 [pii] AID - 10.1016/j.euroneuro.2007.05.002 [doi] PST - ppublish SO - Eur Neuropsychopharmacol. 2008 Feb;18(2):128-40. doi: 10.1016/j.euroneuro.2007.05.002. Epub 2007 Jun 12.