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

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

  • Acta Pharmacol Sin. 2020 Feb;41(2):173-180. doi: 10.1038/s41401-019-0296-7.
Yan-Hang Wang 1 Hai-Ning Lv 1 Qing-Hua Cui 2 Peng-Fei Tu 1 Yong Jiang 3 Ke-Wu Zeng 4
Affiliations

Affiliations

  • 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.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. yongjiang@bjmu.edu.cn.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. ZKW@bjmu.edu.cn.
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.

Keywords

NLRP3 inflammasome pathway; dopamine D1/2 receptors; inflammatory mediators; isosibiricin; natural product; neuroinflammation.

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