2. Academic Validation
  3. Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression

Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression

  • J Neuroinflammation. 2021 Feb 1;18(1):38. doi: 10.1186/s12974-021-02091-5.
Weifen Li 1,  Tahir Ali 1,  Chengyou Zheng 1,  Zizhen Liu 1,  Kaiwu He 1,  Fawad Ali Shah 1 2,  Qingguo Ren 3,  Shafiq Ur Rahman 1 4,  Ningning Li 5,  Zhi-Jian Yu 6,  Shupeng Li 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 2 Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, Islamabad, Pakistan.
  • 3 Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 4 Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal, Dir, 18000, Pakistan.
  • 5 Tomas Lindahl Nobel Laureate Laboratory, Precision Medicine Research Centre, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
  • 6 Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, The 6th Affiliated Hospital of Shenzhen University Health Science Center, No 89, Taoyuan Road, Nanshan District, Shenzhen, 518052, China. yuzhijiansmu@163.com.
  • 7 State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. lisp@pku.edu.cn.
  • 8 Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. lisp@pku.edu.cn.
  • 9 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. lisp@pku.edu.cn.
PMID: 33526073 DOI: 10.1186/s12974-021-02091-5
Abstract

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.

Keywords

Depression; Fluoxetine; HDAC1-eEF2; Neuroinflammation; Synaptogenesis.

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