1,2,4-Trimethoxybenzene ameliorates depression-like behaviors by inhibiting the activation of NLRP3 inflammasome

Abstract

Our previous works identified that 1,2,4-Trimethoxybenzene (1,2,4-TTB) is an NOD-like receptor (NLR) family pyrin domain-containing-3 (NLRP3) inflammasome-specific inhibitor and ameliorates the severity of experimental autoimmune encephalomyelitis. This study explored whether 1,2,4-TTB has an antidepressive-like role, which depends on suppressing NLRP3 inflammasome. In the current study, the depression-like behaviors induced by lipopolysaccharide (LPS) or fear conditioning were used to determine the antidepressive-like role of 1,2,4-TTB. The results showed that NLRP3 inflammasome is activated in the hippocampus by repetitive injection of LPS. 1,2,4-TTB attenuates the depression-like behaviors and suppresses hippocampal NLRP3 inflammasome activation in LPS-induced depression model mice. In addition, we proved that 1,2,4-TTB enhances the fear memory extinction and alleviates anxiety- and depression-like behavior in mice stimulated by fear conditioning. Consistently,1,2,4-TTB inhibited the activation of hippocampal NLRP3 inflammasome in mice subjected to fear conditioning. Therefore, our study demonstrates that 1,2,4-TTB mitigates depression-like behaviors, depending on its inhibitory role in NLRP3 inflammasome activation.