期刊
NEUROCHEMICAL RESEARCH
卷 43, 期 2, 页码 387-396出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-017-2433-3
关键词
Duloxetine; Antidepressant; Nrf2; Heme oxigenase1; Akt
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- FAPESC [TO 22.333/2010-6]
- Rede IBN-Net/CNPq [IBN 01.06.0842-00]
- CAPES-PROCAD
- CAPES-REUNI
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-CAPES
- INCT-National Institute of Science and Technology for Excitotoxicity and Neuroprotection
The contribution of oxidative stress to the pathophysiology of depression has been described in numerous studies. Particularly, an increased production of reactive oxygen species (ROS) caused by mitochondrial dysfunction can lead to neuronal cell death. Human neuroblastoma SH-SY5Y cells were used to investigate the neuroprotective effect of the antidepressant duloxetine against rotenone-induced oxidative stress. SH-SY5Y cells were pretreated with duloxetine (1-5 mu M) for 24 h followed by a 24-h rotenone exposure (10 mu M). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 (10 mu M) and the heme oxygenase 1 (HO-1) inhibitor zinc protoporphyrin IX-ZnPP (5 mu M) were added to cultures 1 h prior duloxetine treatments. After treatments cell viability and ROS generation were assessed. NF-E2-related factor-2 (Nrf2) nuclear translocation was assessed by immunofluorescent staining after 4 and 8 h of duloxetine incubation. Furthermore, the Nrf2 and HO-1 mRNA expression was carried out after 4-48 h of duloxetine treatment by qRT-PCR. Duloxetine pretreatment antagonized rotenone-induced overproduction of ROS and cell death in SH-SY5Y cells. In addition, a 1-h pretreatment with LY294002 abolished duloxetine's protective effect. Duloxetine also induced nuclear translocation of the Nrf2 and the expression of its target gene, HO-1. Finally, the HO-1 inhibitor, ZnPP, suppressed the duloxetine protective effect. Overall, these results indicate that the mechanism of duloxetine neuroprotective action against oxidative stress and cell death might rely on the Akt/Nrf2/HO-1 pathways.
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