A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells

作者：Li, De-Chuan; Bao, Xiu-Qi; Wang, Xiao-Liang; Sun, Hua; Zhang, Dan^*

来源：Naunyn-Schmiedeberg's Archives of Pharmacology, 2017, 390(6): 643-650.

DOI：10.1007/s00210-017-1363-6

• High mobility group box 1
• FLZ
• Neuroinflammation
• Microglia
• Parkinson's disease

High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson's disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ's effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-kappa B signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-kappa B signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson's disease.

• 出版日期2017-6
• 单位中国医学科学院北京协和医院; 北京协和医学院; 天然药物活性物质与功能国家重点实验室