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

• Published in: Acta pharmacologica Sinica 2020-02, Vol.41 (2), p.173-180
• Main Authors: Wang, Yan-hang, Lv, Hai-ning, Cui, Qing-hua, Tu, Peng-fei, Jiang, Yong, Zeng, Ke-wu
• Format: Article
• Language: English
• Subjects: Animals; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Caspase 1 - metabolism; Caspase-1; Cell Line; Coumarin; Cytokines; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dose-Response Relationship, Drug; IL-1β; Immunology; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Interleukin 18; Interleukin 6; Internal Medicine; Lipopolysaccharides; Medical Microbiology; Medicinal plants; Mice; Mice, Inbred BALB C; Microglia; Microglia - drug effects; Microglia - metabolism; Neurological diseases; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pharmacology/Toxicology; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Risk factors; Signal transduction; Signal Transduction - drug effects; Therapeutic applications; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0296-7

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 (10−50 μM) 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 (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-1β. Collectively, this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.