Inhibition of the TLR4/NF-κB/TNF-α axis by TAK-242 or PDTC reduces central nervous system inflammation to alleviate lipopolysaccharide induced sickness behaviors in mice

Background: During the pathogenic microorganisms infection, animals will exhibit sickness behaviors, yet there is a lack of sufficient research on the pathogenesis of sickness behaviors and related treatments. We aim to ascertain the molecular mechanisms of lipopolysaccharide (LPS)-induced sickness behaviors and to find potential therapeutic methods.Methods: In this study, the mice with sickness behaviors elicited by LPS were utilized as the case group and the LPS-exposed mice treated with TAK-242 and PDTC were adopted as the treatment groups (TAK-242+LPS and PDTC+LPS), with PBS-treated mice as the control group. Expression patterns of nucleic acids, cytokines, or pathways were detected by transcriptome-wide analysis of hippocampal samples, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and Western blot assay.Results: Our results demonstrated marked cognitive dysfunction and emotional disorders in the LPS-induced sickness model mice, accompanied by activation of microglia and astrocytes in the hippocampus. RNAseq results showed 524 up-regulated genes and 126 down-regulated genes in the hippocampal tissues. Among them, 108 DEGs were involved in signal transduction, and NF-kappa B (NF-κB), Toll-like receptor (TLR), and TNF-α pathways were the pathways enriched with the largest number of genes. LPS-exposed mice were treated with two pathway inhibitors, TAK-242 and PDTC, respectively. Both of the two could significantly ameliorate the cognitive dysfunction caused by LPS, notably block the microglial activation in the hippocampus, and reduce the levels of neuroinflammatory factors such as IL-1a, IL-6, and TNF-α.Conclusion: Our results suggest that the TLR4/NF-κB/TNF-α axis may be a potential mechanism by which LPS-triggered neuroinflammation leads to sickness behaviors and that inhibitors TAK-242 and PDTC have potential therapeutic value.