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

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

  • Biomed Pharmacother. 2024 Mar 1:173:116342. doi: 10.1016/j.biopha.2024.116342.
Qianqian Ruan 1 Yanan Geng 2 Ming Zhao 2 Heyang Zhang 2 Xiang Cheng 2 Tong Zhao 2 Xiangpei Yue 2 Xiufang Jiang 2 Xiaoxia Jiang 2 Xiao-Yu Hou 3 Ling-Ling Zhu 4
Affiliations

Affiliations

  • 1 Beijing Institute of Basic Medical Sciences, Beijing 100850, China; State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China; Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 2 Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
  • 3 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China. Electronic address: xyhou@cpu.edu.cn.
  • 4 Beijing Institute of Basic Medical Sciences, Beijing 100850, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China. Electronic address: linglingzhuamms@126.com.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

BNIP3; FG-4592; Hippocampus; Hypoxia-inducible factor 1; Microglia; Neuroinflammation; Neuropsychiatric diseases; Prolyl hydroxylase; Transcriptome sequencing.

Figures
Products