Details

Autor(en) / Beteiligte

• Ruan, Qianqian
• Geng, Yanan
• Zhao, Ming
• Zhang, Heyang
• Cheng, Xiang
• Zhao, Tong
• Yue, Xiangpei
• Jiang, Xiufang
• Jiang, Xiaoxia
• Hou, Xiao-Yu
• Zhu, Ling-Ling

Titel

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

Ist Teil von

• Biomedicine & pharmacotherapy, 2024-04, Vol.173, p.116342-116342, Article 116342

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.