1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis

• 作者: Rui-yuan Pan Xiang-xi Kong Yong Cheng Lu Du Zhen-chao Wang Chao Yuan Jin-bo Cheng Zeng-qiang Yuan Hai-yan Zhang Ya-jin Liao
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: Article Neuropharmacology
• 页码范围: 1769-1779
• 页数: 11页
• 语种: 英文

摘要

NOD-like receptor (NLR) family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in inflammation-associated diseases such as multiple sclerosis,Parkinson's disease,and stroke.Targeting the NLRP3 inflammasome is beneficial to these diseases,but few NLRP3 inflammasome-selective inhibitors are identified to date.Essential oils (EOs) are liquid mixtures of volatile and low molecular-weight organic compounds extracted from aromatic plants,which show various pharmacological activities,including antibacterial,antifungal,antiviral,antioxidant,and anti-inflammatory properties.In this study we screened active ingredients from essential oils,and identified 1,2,4-trimethoxybenzene (1,2,4-TTB) as a selective NLRP3 inflammasome inhibitor.We showed that 1,2,4-TTB (1 mM) markedly suppressed nigericin-or ATP-induced NLRP3 inflammasome activation,thus decreased caspase-1 activation and IL-1β secretion in immortalized murine bone marrow-derived macrophages (iBMDMs) and in primary mouse microglia.Moreover,1,2,4-TTB specifically inhibited the activation of NLRP3 inflammasome without affecting absent in melanoma 2(AIM2) inflammasome activation.We further demonstrated that 1,2,4-TTB inhibited oligomerization of the apoptosis-associated speck-like protein containing a CARD (ASC) and protein-protein interaction between NLRP3 and ASC,thus blocking NLRP3 inflammasome assembly in iBMDMs and in primary mouse macrophages.In mice with experimental autoimmune encephalomyelitis (EAE),administration of 1,2,4-TTB (200 mg· kg-1· d-1,i.g.for 17 days) significantly ameliorated EAE progression and demyelination.In conclusion,our results demonstrate that 1,2,4-TTB is an NLRP3 inflammasome inhibitor and attenuates the clinical symptom and inflammation of EAE,suggesting that 1,2,4-TTB is a potential candidate compound for treating NLRP3 inflammasome-driven diseases,such as multiple sclerosis.