Prolyl hydroxylase inhibitor FG-4592 alleviates neuroinflammation via HIF-1/BNIP3 signaling in microglia

• Published in: Biomedicine & pharmacotherapy Vol. 173; p. 116342
• Main Authors: Ruan, Qianqian, Geng, Yanan, Zhao, Ming, Zhang, Heyang, Cheng, Xiang, Zhao, Tong, Yue, Xiangpei, Jiang, Xiufang, Jiang, Xiaoxia, Hou, Xiao-Yu, Zhu, Ling-Ling
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2024; Elsevier
• Subjects: Animals; BNIP3; FG-4592; Hippocampus; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - metabolism; Lipopolysaccharides - metabolism; Lipopolysaccharides - toxicity; Mice; Microglia; Microglia - metabolism; Neuroinflammation; Neuroinflammatory Diseases; Neuropsychiatric diseases; NF-kappa B - metabolism; Prolyl hydroxylase; Prolyl-Hydroxylase Inhibitors - metabolism; Signal Transduction; Transcriptome sequencing; Hypoxia-inducible factor 1; HIF; EPO; Glut 1; VEGF; BNIP3; Neuropsychiatric diseases; FG-4592; Neuroinflammation; Transcriptome sequencing; IL-1β; PHD; CID/MS; IL-6; LPS; Microglia; DMEM; NF-κB; SiBNIP3; TNF-α; Prolyl hydroxylase; Hippocampus; ELISA
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116342

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. 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. 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. 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. •FG-4592 can transports across the blood-brain barrier into the mouse brain.•FG-4592 pretreatment significantly alleviated the neuroinflammation induced by LPS in vivo and in vitro.•FG-4592 upregulation HIF-1/BNIP3 signaling pathway to play the anti-inflammation role.•FG-4592 acts as a neuroprotective agent to protect against neuropsychiatric diseases induced by neuroinflammation.