%0 Journal Article
%T Prolyl hydroxylase inhibitor FG-4592 alleviates neuroinflammation via HIF-1/BNIP3 signaling in microglia.
%A Ruan Q
%A Geng Y
%A Zhao M
%A Zhang H
%A Cheng X
%A Zhao T
%A Yue X
%A Jiang X
%A Jiang X
%A Hou XY
%A Zhu LL
%J Biomed Pharmacother
%V 173
%N 0
%D 2024 Apr 1
%M 38430635
%F 7.419
%R 10.1016/j.biopha.2024.116342
%X <B>BACKGROUND: </B>Neuroinflammation is responsible for neuropsychiatric dysfunction following acute brain injury and neurodegenerative diseases. This study describes how a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor FG-4592 prevents the lipopolysaccharide (LPS)-induced acute neuroinflammation in microglia.<BR><B>METHODS: </B>The distribution of FG-4592 in mouse brain tissues was determined by collision-induced dissociation tandem mass spectrometry. Microglial activation in the hippocampus was analyzed by immunofluorescence. Moreover, we determined the activation of HIF-1 and nuclear factor-κB (NF-κB) signaling pathways, proinflammatory responses using molecular biological techniques. Transcriptome sequencing and BNIP3 silencing were conducted to explore signaling pathway and molecular mechanisms underlying FG-4592 anti-inflammatory activity.<BR><B>RESULTS: </B>FG-4592 was transported into the brain tissues and LPS increased its transportation. FG-4592 promoted the expression of HIF-1α and induced the downstream gene transcription in the hippocampus. Administration with FG-4592 significantly inhibited microglial hyperactivation and decreased proinflammatory cytokine levels following LPS treatment in the hippocampus. The LPS-induced inflammatory responses and the NF-κB signaling pathway were also downregulated by FG-4592 pretreatment in microglial cells. Mechanistically, Venn diagram analysis of transcriptomic changes of BV2 cells identified that BNIP3 was a shared and common differentially expressed gene among different treatment groups. FG-4592 markedly upregulated the protein levels of BNIP3 in microglia. Importantly, BNIP3 knockdown aggravated the LPS-stimulated inflammatory responses and partially reversed the protection of FG-4592 against microglial inflammatory signaling and microglial activation in the mouse hippocampus.<BR><B>CONCLUSIONS: </B>FG-4592 alleviates neuroinflammation through facilitating microglial HIF-1/BNIP3 signaling pathway in mice. Targeting HIF-PHD/HIF-1/BNIP3 axis is a promising strategy for the development of anti-neuroinflammation drugs.