Paeonol prevents sepsis-associated encephalopathy via regulating the HIF1A pathway in microglia

Paeonol, a phenolic acid compound extracted from the Cortex Moutan, exhibits significant anti-inflammatory, antioxidant, and anti-apoptotic properties. This study aimed to investigate the effects of paeonol on neuroinflammation and depressive-like symptoms, and the underlying mechanisms in a mouse model of sepsis-associated encephalopathy (SAE) induced by lipopolysaccharide (LPS). To assess the therapeutic potential of paeonol in mice treated with LPS, behavioral assessments were conducted using the open-field test (OFT), tail suspension test (TST), and forced swimming test (FST), and quantitative PCR (qPCR), Western blot, and immunofluorescent staining were utilized to determine the expression levels of inflammatory molecules in the hippocampus in vivo and microglial cells in vitro. Our results revealed that paeonol significantly alleviated anxiety and depressive-like symptoms, as evidenced by improved activity in OFT, reduced immobility time in TST and FST, and decreased levels of inflammatory markers such as IL6, TNFα, and PFKFB3. Further in vitro experiments confirmed that paeonol downregulated the expression of pro-inflammatory molecules. A network pharmacology-based strategy combined with molecular docking and cellular thermal shift assay highlighted HIF1A as a potential target for paeonol. Similar anti-inflammatory effects of a HIF1A inhibitor were also observed in microglia treated with LPS. Furthermore, these effects were reversed by CoCl₂, a HIF1A agonist, indicating the critical role of the HIF1A signaling pathway in mediating the therapeutic effects of paeonol. These findings highlight the potential of paeonol in modulating the HIF1A pathway, offering a promising therapeutic strategy for neuroinflammation in SAE.