Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression.
Int J Neuropsychopharmacol
; 19(9)2016 Sep.
Article
in En
| MEDLINE
| ID: mdl-27207922
ABSTRACT
BACKGROUND:
Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Fluoxetine, a widely used antidepressant, has been shown to have potential antiinflammatory activity, but the underlying mechanisms remain obscure.METHODS:
We used a chronic mild stress model and cultured primary macrophage/microglia to investigate the effects of fluoxetine on NLRP3 inflammasome and its underlying mechanisms.RESULTS:
We demonstrated that fluoxetine significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1ß secretion in both peripheral macrophages and central microglia. We further found that ï¬uoxetine reduced reactive oxygen species production, attenuated the phosphorylation of double-stranded RNA-dependent protein kinase, and inhibited the association of protein kinase with NLRP3. These data indicate that fluoxetine inhibits the activation of NLRP3 inflammasome via downregulating reactive oxygen species-protein kinase-NLRP3 signaling pathway. Correspondingly, in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior.CONCLUSIONS:
Our findings reveal that fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the potential clinical use of fluoxetine in NLRP3 inflammasome-driven inflammatory diseases such as depression.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Int J Neuropsychopharmacol
Journal subject:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Year:
2016
Document type:
Article