Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway  

作　　者：Yan-hang Wang Hai-ning Lv Qing-hua Cui Peng-fei Tu Yong Jiang Ke-wu Zeng 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [2]School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China

出　　处：《Acta Pharmacologica Sinica》2020年第2期173-180,共8页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(Numbers 81773932,81530097 and 81222051);the Drug Innovation Major Project(Number 2018ZX09711001-008-003).

摘　　要：Microglia-mediated neuroinflammation is a crucial risk factor for neurological disorders.Recently,dopamine receptors have been found to be involved in multiple immunopathological processes and considered as valuable therapeutic targets for inflammation-associated neurologic diseases.In this study we investigated the anti-neuroinflammation effect of isosibiricin,a natural coumarin compound isolated from medicinal plant Murraya exotica.We showed that isosibiricin(10?50μM)dose-dependently inhibited lipopolysaccharide(LPS)-induced BV-2 microglia activation,evidenced by the decreased expression of inflammatory mediators,including nitrite oxide(NO),tumour necrosis factor-α(TNF-α),interleukin-6(IL-6),interleukin-1β(IL-1β)and interleukin-18(IL-18).By using transcriptomics coupled with bioinformatics analysis,we revealed that isosibiricin treatment mainly affect dopamine receptor signalling pathway.We further demonstrated that isosibiricin upregulated the expression of dopamine D1/2 receptors in LPS-treated BV-2 cells,resulting in inhibitory effect on nucleotide binding domain-like receptor protein 3(NLRP3)/caspase-1 inflammasome pathway.Treatment with dopamine D1/2 receptor antagonists SCH 23390(1μM)or sultopride(1μM)could reverse the inhibitory effects of isosibiricin on NLRP3 expression as well as the cleavages of caspase-1 and IL-1β.Collectively,this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.

关 键 词：isosibiricin natural product NEUROINFLAMMATION DOPAMINE D1/2 receptors inflammatory MEDIATORS NLRP3 INFLAMMASOME PATHWAY 

分 类 号：R285.5[医药卫生—中药学]