1, 2, 4-trimethoxybenzene alleviates pain and related psychiatric disorders by inhibiting NLRP3 inflammasome activation

Abstract

Pain and pain-related psychiatric diseases affect approximately one-third of the global population, and effective treatment remains a lack of options. NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is regarded as a potential therapeutic target for managing pain and related psychiatric diseases. Our previous research reported that 1,2,4-trimethoxybenzene (1,2,4-TTB) effectively inhibited NLRP3 inflammasome activity. Therefore, we further investigated the role of 1,2,4-TTB in the treatment of pain and its associated psychiatric disorders. In this study, we evaluated the effects of 1,2,4-TTB (200 mg.kg⁻¹) by intragastric administration on mechanical pain, anxiety and depression-like behaviors using Complete Freund’s Adjuvant (CFA) induced acute and chronic inflammatory pain mouse models. Furthermore, NLRP3 inflammasome activation was assessed through western blotting. Immunofluorescence was employed to observe the number of macrophages and microglia. Results indicated that 1,2,4-TTB markedly relieved mechanical pain in acute and chronic pain mouse models. 1,2,4-TTB also improved anxiety and depression-like behaviors in pain mouse models. Additionally, NLRP3 inflammasome activation was dramatically suppressed by 1,2,4-TTB in pain mouse models. The macrophage and microglia activation were also inhibited by 1,2,4-TTB. Our research shows that 1,2,4-TTB attenuates both acute and chronic inflammatory pain as well as anxiety and depression-like behaviors. These findings suggest that 1,2,4-TTB is a promising therapeutic option for managing various types of pain, anxiety, and depression.