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A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway.

ABSTRACT: Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

SUBMITTER: Nguyen PL

PROVIDER: S-EPMC7959294 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neurodegenerative disorders are known to be associated with neuroinflammation caused by microglia. Therefore, regulation of microglia activation and polarization to inhibit neuroinflammatory reactions seems to hold promise as a therapeutic approach in neurodegenerative disorders. Spatholobus suberectus Dunn (SSD) has been utilized as a traditional Chinese medicine remedy for brain diseases for thousands of years. SSD possesses various pharmacological activities, such as circulation invigoration, neuroprotection, and anti-inflammatory. The objective of this research was to examine the anti-neuroinflammatory effects and molecular mechanisms of an active fraction from SSD (ASSD) in vitro culture BV2 cells, a type of mouse microglia cell line. The inflammatory responses in BV2 cells were induced by stimulating them with 1 μg/mL lipopolysaccharide (LPS) and the effects of ASSD on LPS-stimulated inflammation were monitored. Besides, by using the methods of Western blot, immunofluorescence, and RT-PCR, the mechanisms of ASSD on microglia activation, M1/M2 polarization, and the TLR4/MyD88/NF-κB pathway were investigated. Our findings demonstrate that the treatment doses of ASSD neither induce cytotoxicity nor promote the production of inflammatory cytokines. In addition, immunofluorescence analysis show that ASSD inhibited the expression of ionized calcium-binding adapter molecule 1(Iba1) and inducible nitricoxide synthase (iNOS), and induced arginase 1 (Arg1) expression. Moreover, Western blot analysis indicated that ASSD significantly down-regulated TLR4, MyD88, p-IκB, NF-κB p65, and NF-κB p-p65 protein expression levels. Furthermore, RT-qPCR assay show that ASSD significantly down-regulated iNOS, TLR4, MyD88, and NF-κB mRNA expression levels, and up-regulated Arg1 mRNA expression level. According to the findings, ASSD can suppress microglia-mediated inflammatory responses by modulating microglia activation, inducing a shift from M1 to M2 polarization, and inhibiting the TLR4/MyD88/NF-κB signaling pathway.

Dataset Information

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway.

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