2. Academic Validation
  3. 1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis

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

  • Acta Pharmacol Sin. 2021 Nov;42(11):1769-1779. doi: 10.1038/s41401-021-00613-8.
Rui-Yuan Pan # 1 2,  Xiang-Xi Kong # 2,  Yong Cheng 1,  Lu Du 2,  Zhen-Chao Wang 3,  Chao Yuan 2,  Jin-Bo Cheng 1,  Zeng-Qiang Yuan 2,  Hai-Yan Zhang 4,  Ya-Jin Liao 5 6 7 8
Affiliations

Affiliations

  • 1 Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China.
  • 2 Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
  • 3 Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
  • 4 Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. haiyansl@163.com.
  • 5 Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China. lyajin@muc.edu.cn.
  • 6 Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. lyajin@muc.edu.cn.
  • 7 Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. lyajin@muc.edu.cn.
  • 8 NHC Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410005, China. lyajin@muc.edu.cn.
  • # Contributed equally.
PMID: 33627802 DOI: 10.1038/s41401-021-00613-8
Abstract

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.

Keywords

1,2,4-Trimethoxybenzene; ASC; NLRP3 inflammasome; essential oils; experimental autoimmune encephalomyelitis.

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