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

• 来源期刊: 中国药理学报（英文版）
• 关键词: isosibiricin natural product neuroinflammation dopamine D1/2 receptors inflammatory mediators NLRP3 inflammasome pathway
• 年，卷（期）: 2020,（2）
• 页码范围: 173-180
• 页数: 8页
• 语种: 英文

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 inflammationassociated 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 (10-50 μM) dose-dependently inhibited lipopolysaccharide (LPS)-induced BV-2 microglia activation,evidenced by the decreased expression of inflammatory mediators,including nitrite oxide (NO),tumout necrosis factor-α (TNF-α),interleukin-6 (IL-6),interleukin-1 β (IL-1 β) 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 (1 μM) or sultopride (1 μM) could reverse the inhibitory effects of isosibiricin on NLRP3 expression as well as the cleavages of caspase-1 and IL-1 β.Collectively,this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.