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

Abstract

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.

Natural Products for the Treatment of Post-stroke Depression

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Discovery of Active Ingredients Targeted TREM2 by SPR Biosensor-UPLC/MS Recognition System, and Investigating the Mechanism of Anti-Neuroinflammatory Activity on the Lignin-Amides from Datura metel Seeds

“…The BV2 microglia model induced by LPS is used as one of the commonly used cell models. The principal pathways of inflammation include TLR4/MyD88, NLRP3/Caspase1, and TREM2/DAP12 pathways, and so on [ 7 , 9 , 12 , 34 , 35 , 36 ]. In this study, an LPS induced microglia inflammatory cell model was used to study the inhibitory effect of lignan-amides in Datura metel seeds on the release of inflammatory factor NO.…”

Herniarin, Dimethylfraxetin and Extracts from Tagetes lucida, in Psychosis Secondary to Ketamine and Its Interaction with Haloperidol

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