1,2,4-Trimethoxybenzene

1,2,4-Trimethoxybenzene is an orally active NLRP3 selective inhibitor. 1,2,4-Trimethoxybenzene can markedly suppress Nigericin (HY-127019) or ATP (HY-B2176)-induced NLRP3 inflammasome activation, thus decreasing caspase-1 activation and IL-1β secretion. 1,2,4-Trimethoxybenzene specifically inhibits the activation of NLRP3 inflammasome without affecting absent in melanoma 2 (AIM2) inflammasome activation. 1,2,4-Trimethoxybenzene inhibits 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. 1,2,4-Trimethoxybenzene can be used for the study of experimental autoimmune encephalomyelitis (EAE), multiple sclerosis, and type 2 diabetes^[1][2][3]. In Vitro:1,2,4-Trimethoxybenzene (0.5-1 mM, 1.5 h) significantly inhibits Nigericin (HY-127019) and Lipopolysaccharides (HY-D1056) (LPS)-induced NLRP3 inflammasome activation in immortalized murine bone marrow-derived macrophages (iBMDMs), manifested as reduced caspase-1 (Casp-1) cleavage and IL-1β secretion^[1].
1,2,4-Trimethoxybenzene (1 mM, 75-90 min) inhibits LPS and ATP-induced NLRP3 activation in iBMDMs, primary microglia, and Primary macrophages cells^[1].
1,2,4-Trimethoxybenzene (75-90 min) inhibits nigericin-induced NLRP3 activation in iBMDMs and primary macrophages, while 1,2,3-TTB had no inhibitory effect, indicating that the inhibitory activity is structure-dependent^[1].
1,2,4-Trimethoxybenzene (45 min-2 h) does not inhibit LPS and poly(dA:dT)-induced activation of AIM2 inflammasome in primary peritoneal macrophages and iBMDMs^[1].
1,2,4-Trimethoxybenzene (1 h) reduces the formation of ASC specks in iBMDMs and Primary microglia induced by LPS and nigericin: immunofluorescence showed a significant reduction in the number of ASC specks; DSS crosslinking experiments showed an increase in soluble ASCs and a decrease in insoluble ASCs^[1].
1,2,4-Trimethoxybenzene (1 h) blocks the protein-protein interaction between NLRP3 and ASC in LPS-induced iBMDMs^[1].
1,2,4-Trimethoxybenzene (1 h) inhibits LPS and nigericin-induced NLRP3 oligomerization of iBMDMs and primary macrophages: DSS crosslinking experiments showed reduced formation of NLRP3 monomers, dimers and higher oligomers^[1].
In Vivo:1,2,4-Trimethoxybenzene (200 mg/kg, p.o., once daily for 17 days) significantly alleviates clinical symptoms, weight loss, and demyelinating pathology in EAE model mice^[1].
1,2,4-Trimethoxybenzene (50-100 mg/kg, p.o., once daily for 3 days) enhances the extinction of fear memories and alleviates PTSD-related anxiety and depression-like behaviors in mice by inhibiting the NLRP3 inflammasome^[2].
1,2,4-Trimethoxybenzene (50-200 mg/kg, p.o., once daily for 8 weeks) improves T2DM-related cognitive dysfunction by inhibiting NLRP3 inflammasome activation and regulating gut microbiota in type 2 diabetic rats^[3].