Roxadustat (FG-4592) abated lipopolysaccharides-induced depressive-like symptoms via PI3K signaling

Axiang Li; Zizhen Liu; Tahir Ali; Ruyan Gao; Yanhua Luo; Qichao Gong; Chenyou Zheng; Weifen Li; Hongling Guo; Xinshe Liu; Shupeng Li; Tao Li

doi:10.3389/fnmol.2023.1048985

Roxadustat (FG-4592) abated lipopolysaccharides-induced depressive-like symptoms via PI3K signaling

Front Mol Neurosci. 2023 Mar 15:16:1048985. doi: 10.3389/fnmol.2023.1048985. eCollection 2023.

Authors

Axiang Li^{1

2

3}, Zizhen Liu³, Tahir Ali^{3

4}, Ruyan Gao³, Yanhua Luo³, Qichao Gong³, Chenyou Zheng³, Weifen Li³, Hongling Guo³, Xinshe Liu^{1

2

5}, Shupeng Li^{3

4

6}, Tao Li^{1

2

5}

Affiliations

¹ College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
² Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
⁴ Shenzhen Bay Laboratory, Institute of Chemical Biology, Shenzhen, China.
⁵ NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
⁶ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Abstract

Background: Despite its role in inflammation and the redox system under hypoxia, the effects and molecular mechanisms of hypoxia-inducible factor (HIF) in neuroinflammation-associated depression are poorly explored. Furthermore, Prolyl hydroxylase domain-containing proteins (PHDs) regulate HIF-1; however, whether and how PHDs regulate depressive-like behaviors under Lipopolysaccharides (LPS)-induced stress conditions remain covered.

Methods: To highlight the roles and underlying mechanisms of PHDs-HIF-1 in depression, we employed behavioral, pharmacological, and biochemical analyses using the LPS-induced depression model.

Results: Lipopolysaccharides treatment induced depressive-like behaviors, as we found, increased immobility and decreased sucrose preference in the mice. Concurrently, we examined increased cytokine levels, HIF-1 expression, mRNA levels of PHD1/PHD2, and neuroinflammation upon LPS administration, which Roxadustat reduced. Furthermore, the PI3K inhibitor wortmannin reversed Roxadustat-induced changes. Additionally, Roxadustat treatment attenuated LPS-induced synaptic impairment and improved spine numbers, ameliorated by wortmannin.

Conclusion: Lipopolysaccharides-dysregulates HIF-PHDs signaling may contribute to neuroinflammation-coincides depression via PI3K signaling.

Keywords: HIF-PHD/PI3K; Neuroinflammation; depression; lipopolysaccharides; roxadustat (FG-4592).