Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell.
Fluoxetine is a widely used antidepressant compound which inhibits the reuptake of serotonin in the central nervous system. Recent studies have shown that fluoxetine can promote neurogenesis and improve the survival rate of neurons. However, whether fluoxetine modulates the proliferation or neuroprotection effects of neural stem cells (NSCs) needs to be elucidated. In this study, we demonstrated that 20 microM fluoxetine can increase the cell proliferation of NSCs derived from the hippocampus of adult rats by MTT test. The up-regulated expression of Bcl-2, Bcl-xL and the cellular FLICE-inhibitory protein (c-FLIP) in fluoxetine-treated NSCs was detected by real-time RT-PCR. Our results further showed that fluoxetine protects the lipopolysaccharide-induced apoptosis in NSCs, in part, by activating the expression of c-FLIP. Moreover, c-FLIP induction by fluoxetine requires the activation of the c-FLIP promoter region spanning nucleotides -414 to -133, including CREB and SP1 sites. This effect appeared to involve the phosphatidylinositol-3-kinase-dependent pathway. Furthermore, fluoxetine treatment significantly inhibited the induction of proinflammatory factor IL-1beta, IL-6, and TNF-alpha in the culture medium of LPS-treated NSCs (p<0.01). The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that fluoxentine increased the functional production of serotonin in NSCs. Together, these data demonstrate the specific activation of c-FLIP by fluoxetine and indicate the novel role of fluoxetine for neuroprotection in the treatment of depression.
Department of Medical Research and Education, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan. shchiou@vghtpe.gov.tw
Shih-Hwa
SH
Chiou
Shih-Jen
SJ
Chen
Chi-Hsien
CH
Peng
Yu-Li
YL
Chang
Hung-Hai
HH
Ku
Wen-Ming
WM
Hsu
Larry L-T
LL
Ho
Chen-Hsen
CH
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; D008070:Lipopolysaccharides; D005473:Fluoxetine; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases