Tetramethoxystilbene Inhibits Nlrp3 Inflammasome Assembly Via Blocking The Oligomerization Of Apoptosis-Associated Speck-Like Protein Containing Caspase Recruitment Domain: In Vitro And In Vivo Evaluation

Nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome complex regulates the caspase-1 activity and subsequent processing of interleukin-1 beta (IL-1 beta). Various inflammatory diseases involve the activation of inflammasome complexes; thus, the intervention in complex formation via small molecules offers a new therapeutic opportunity. The structure-guided design and synthesis of a series of methoxystilbenes and methoxy-2-phenylnaphthalenes identified new inhibitors of NLRP3 inflammasome complex. The tetramethoxystilbene 4o and trimethoxy 2-phenylnaphthalene 1t inhibit the release of a mature form of IL-1 beta in J774A.1 cells with IC50 values of 1.39 and 2.07 mu M, respectively. Mechanistic investigation revealed that tetramethoxystilbene 4o blocks the oligomerization of apoptosis-associated speck-like protein (ASC), which is the vital step in the formation of NLRP3 inflammasome assembly, thus preventing the activation of caspase-1 and the IL-1 beta release. Treatment of LPS+ATP challenged mice with 20 mg/kg of 4o significantly suppressed the levels of IL-1 beta. The data presented herein warrant further investigation of methoxystilbenes in disease-specific models of inflammatory diseases.