title: Desipramine protects neuronal cell death and induces heme oxygenase-1 expression in Mes23.5 dopaminergic neurons.
abstract: BACKGROUND
  Desipramine is known principally as a tricyclic antidepressant drug used to promote recovery of depressed patients. It has also been used in a number of other psychiatric and medical conditions. The present study is the first to investigate the neuroprotective effect of desipramine.
  
  
  RESULTS
  Mes23.5 dopaminergic cells were used to examine neuroprotective effect of desipramine. Western blot, reverse transcription-PCR, MTT assay, siRNA transfection and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of desipramine. Desipramine induces endogenous anti-oxidative enzyme, heme oxygenase-1 (HO-1) protein and mRNA expression in concentration- and time-dependent manners. A different type of antidepressant SSRI (selective serotonin reuptake inhibitor), fluoxetine also shows similar effects of desipramine on HO-1 expression. Moreover, desipramine induces HO-1 expression through activation of ERK and JNK signaling pathways. Desipramine also increases NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and enhances Nrf2-DNA binding activity. Moreover, desipramine-mediated increase of HO-1 expression is reduced by transfection with siRNA against Nrf2. On the other hand, pretreatment of desipramine protects neuronal cells against rotenone- and 6-hydroxydopamine (6-OHDA)-induced neuronal death. Furthermore, inhibition of HO-1 activity by a HO-1 pharmacological inhibitor, ZnPP IX, attenuates the neuroprotective effect of desipramine. Otherwise, activation of HO-1 activity by HO-1 activator and inducer protect 6-OHDA-induced neuronal death.
  
  
  CONCLUSIONS
  These findings suggest that desipramine-increased HO-1 expression is mediated by Nrf2 activation through the ERK and JNK signaling pathways. Our results also suggest that desipramine provides a novel effect of neuroprotection, and neurodegenerative process might play an important role in depression disorder.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.forename: Bor-Ren
authors.initials: BR
authors.lastname: Huang
authors.forename: Chingju
authors.initials: C
authors.lastname: Lin
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003891:Desipramine / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012235:Rhodamines / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014343:Trypan Blue / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; D012235:Rhodamines; D005473:Fluoxetine; C022027:lissamine rhodamine B; D016627:Oxidopamine; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D014343:Trypan Blue; D003891:Desipramine