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Glycogen synthase kinase-3β regulates anti-inflammatory property of fluoxetine.
MedLine Citation:
PMID:  22749848     Owner:  NLM     Status:  Publisher    
A selective serotonin reuptake inhibitor fluoxetine not only is widely used in the treatment of depression but also has an anti-inflammatory property. Glycogen synthase kinase-3beta (GSK-3β) is a vital factor in the inflammation process. How fluoxetine interferes with inflammation via a GSK-3β-dependent pathway remains unclear. The aim of this study is to investigate the effects of fluoxetine on lipopolysaccharide (LPS)-induced inflammation. Results showed that fluoxetine decreased mortality rate of the mice. It also inhibited LPS-induced release of nitric oxide (NO) and prostaglandin E2 (PGE2) in serum and RAW264.7 murine macrophages and expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Upon LPS stimulation, fluoxetine caused a delay but increased in the phosphorylated levels of GSK-3β (ser9), whereas it did not affect LPS-induced activation of mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS). Fluoxetine in combination with phosphatidylinositol 3-kinases/Akt inhibitors (LY294002 and Wortmannin) did not have a synergistic inhibition on LPS-induced NO release and PGE2 production. In addition, peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9622 showed no reverse effects of this inhibition of fluoxetine. GSK-3β knockdown blocked the inhibitory effects of fluoxetine on LPS-induced iNOS/NO release and COX-2/PGE2 production. These results indicated that GSK-3β regulated anti-inflammatory property of fluoxetine. However, Akt activation, ROS generation, and altered PPARγ activity were not involved in this inhibition of fluoxetine.
Hui-Chen Su; Ching-Ting Ma; Bu-Chin Yu; Yuchieh Chien; Cheng-Chieh Tsai; Wei-Ching Huang; Chiou-Feng Lin; Yeu-Hui Chuang; Kung-Chia Young; Jieh-Neng Wang; Chiung-Wen Tsao
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-29
Journal Detail:
Title:  International immunopharmacology     Volume:  -     ISSN:  1878-1705     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-7-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100965259     Medline TA:  Int Immunopharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan.
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