期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 793, 期 -, 页码 21-27出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2016.10.037
关键词
Antidepressant; Neurite outgrowth; Nrf2; TBE-31; MCE-1; Inflammation
资金
- Minister of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Stony Brook Foundation
- Reata Pharmaceuticals
- Ishidsu Shun Memorial Scholarship (Tokyo, Japan)
- Abbvie
- Dainippon-Sumitomo
- Mochida
- Otsuka
- Taisho
- Institute of Chemical Biology & Drug Discovery Postdoctoral Scholarship
The Nuclear factor (erythroid 2-derived)-like 2 (Nrf2) plays a key role in inflammation which is implicated in the pathophysiology of depression. The Nrf2 activators have antidepressant effects in animal models of depression. The present study was undertaken to examine whether TBE-31 [(+/-)-(4bS,8aR,10aS)-10a-ethyny14-b,8,8-trimethy1-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] and MCE-1 [(+/-)-3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile], the novel Nrf2 activators, could show antidepressant effects in inflammation model of depression. We found that TBE-31 and MCE-1 significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The Nrf2 siRNA, but not negative control of siRNA, significantly blocked the potentiating effects of TBE-31 and MCE-1 on neurite outgrowth in PC12 cells. Furthermore, oral administration of TBE-31 or MCE-1 significantly attenuated an increase in serum levels of tumor necrosis factor-alpha (TNF-alpha) after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In the tail-suspension test and forced swimming test, oral administration of TBE-31 or MCE-1 significantly attenuated an increase in the immobility time after LPS (0.5 mg/kg) administration. These findings suggest that the novel Nrf2 activators such as TBE-31 and MCE-1 might be potential therapeutic drugs for inflammation-related depression.
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