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|標題:||Desipramine Protects Neuronal Cell Death and Induces Heme Oxygenase-1 Expression in Mes23.5 Dopaminergic Neurons||作者:||Lin, Hsiao-Yun
|Project:||PLoS ONE, Volume 7, Issue 11||摘要:||
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.
Methodology/Principal Findings: 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/Significance: 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.
|Appears in Collections:||生命科學系所|
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