2. Academic Validation
  3. 1,2,4-Trimethoxybenzene ameliorates depression-like behaviors by inhibiting the activation of NLRP3 inflammasome

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

  • Int Immunopharmacol. 2025 Apr 4:151:114361. doi: 10.1016/j.intimp.2025.114361.
Yang Zhang 1,  Na Che 2,  Bo Wang 3,  Shuhan Liu 4,  Yuan Dong 4,  Xiangxi Kong 4,  Yige Yun 4,  Shuoshuo Li 5,  Xiao-Qing Tang 6,  Yajin Liao 7
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, P.R. China.Hunan, Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China; Institute of Neuroscience, Hengyang Medical School, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
  • 2 Institute of Neuroscience, Hengyang Medical School, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
  • 3 The First Affiliated Hospital, Institute of Anesthesiology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China.
  • 4 The Brain Science Center, Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing 100850, China.
  • 5 The Brain Science Center, Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing 100850, China. Electronic address: 202202002@bucm.edu.cn.
  • 6 Department of Neurology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, P.R. China.Hunan, Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China; Institute of Neuroscience, Hengyang Medical School, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China. Electronic address: tangxq-usc@usc.edu.cn.
  • 7 Department of Neurology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, P.R. China.Hunan, Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China. Electronic address: lyajin@usc.edu.cn.
PMID: 40031427 DOI: 10.1016/j.intimp.2025.114361
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.

Keywords

1,2,4-trimethoxybenzene; Depression; Fear conditioning; LPS; NLRP3 inflammasome.

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