Journal Article

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

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

2023

Overview

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

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 1-Phosphatidylinositol 3-kinase / Behavior / Cytokines / depression / Gene expression / HIF-PHD/PI3K / Hypotheses / Hypoxia / Inflammation / Laboratory animals / Lipopolysaccharides / Mental depression / Molecular modelling / Molecular Neuroscience / mRNA / Neuroinflammation / Preferences / Prolyl hydroxylase / roxadustat (FG-4592) / Sucrose / Transcription factors / Wortmannin