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Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of
Weifen Li1, Tahir Ali1, Chengyou Zheng1
1State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Background:
Selective serotonin reuptaker inhibitors, including fluoxetine, are widely studied and prescribed antidepressants, while their exact molecular and cellular mechanism are yet to be defined. We investigated the involvement of HDAC1 and eEF2 in the antidepressant mechanisms of fluoxetine using a lipopolysaccharide (LPS)-induced depression-like behavior model.
Methods:
For in vivo analysis, mice were treated with LPS (2 mg/kg BW), fluoxetine (20 mg/kg BW), HDAC1 activator (Exifone: 54 mg/kg BW) and NH125 (1 mg/kg BW). Depressive-like behaviors were confirmed via behavior tests including OFT, FST, SPT, and TST. Cytokines were measured by ELISA while Iba-1 and GFAP expression were determined by immunofluorescence. Further, the desired gene expression was measured by immunoblotting. For in vitro analysis, BV2 cell lines were cultured; treated with LPS, exifone, and fluoxetine; collected; and analyzed.
Results:
Mice treated with LPS displayed depression-like behaviors, pronounced neuroinflammation, increased HDAC1 expression, and reduced eEF2 activity, as accompanied by altered synaptogenic factors including BDNF, SNAP25, and PSD95. Fluoxetine treatment exhibited antidepressant effects and ameliorated the molecular changes induced by LPS. Exifone, a selective HDAC1 activator, reversed the antidepressant and anti-inflammatory effects of fluoxetine both in vivo and in vitro, supporting a causing role of HDAC1 in neuroinflammation allied depression. Further molecular mechanisms underlying HDAC1 were explored with NH125, an eEF2K inhibitor, whose treatment reduced immobility time, altered pro-inflammatory cytokines, and NLRP3 expression. Moreover, NH125 treatment enhanced eEF2 and GSK3β activities, BDNF, SNAP25, and PSD95 expression, but had no effects on HDAC1.
Conclusions:
Our results showed that the antidepressant effects of fluoxetine may involve HDAC1-eEF2 related neuroinflammation and synaptogenesis.
Insights
Fluoxetine
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are common antidepressants.
- Their precise molecular mechanisms remain unclear.
- This study investigates the roles of HDAC1 and eEF2 in fluoxetine's antidepressant action.
Purpose of the Study:
- To elucidate the involvement of HDAC1 and eEF2 in fluoxetine's antidepressant effects.
- To explore the link between neuroinflammation and synaptogenesis in depression models.
Main Methods:
- Utilized a lipopolysaccharide (LPS)-induced depression-like behavior mouse model.
- Administered fluoxetine, HDAC1 activator (Exifone), and eEF2K inhibitor (NH125).
- Assessed behavioral tests, cytokine levels, neuroinflammation markers (Iba-1, GFAP), and protein expression (HDAC1, eEF2, synaptogenic factors).
Main Results:
- LPS induced depression-like behaviors, neuroinflammation, increased HDAC1, and reduced eEF2 activity.
- Fluoxetine ameliorated LPS-induced effects.
- HDAC1 activation reversed fluoxetine's benefits, implicating HDAC1 in neuroinflammation-associated depression.
- NH125 treatment improved depressive behaviors and molecular markers, enhancing eEF2 activity and synaptogenesis.
Conclusions:
- Fluoxetine's antidepressant effects are linked to modulating HDAC1-eEF2 pathways.
- These pathways influence neuroinflammation and synaptogenesis in depression.
