2. Academic Validation
  3. 1,2,4-Trimethoxybenzene alleviates cognitive dysfunction in type 2 diabetes model rats by inhibiting NLRP3 inflammasome and restoring gut microbiota disorders

1,2,4-Trimethoxybenzene alleviates cognitive dysfunction in type 2 diabetes model rats by inhibiting NLRP3 inflammasome and restoring gut microbiota disorders

  • Biochem Pharmacol. 2025 Dec;242(Pt 4):117409. doi: 10.1016/j.bcp.2025.117409.
Ping Zhong 1,  Chang Peng 2,  Yong-Hong Liang 3,  Hui-Chen Huang 4,  Ping Wang 5,  Ming Yang 6,  Hai-Yan Zhang 7
Affiliations

Affiliations

  • 1 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 2 Discipline of Chinese and Western Integrative Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 3 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 4 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 5 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 6 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China. Electronic address: [email protected].
  • 7 State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; Jiangzhong Pharmaceutical Co., Ltd., Nanchang 330100, China. Electronic address: [email protected].
PMID: 41067284 DOI: 10.1016/j.bcp.2025.117409
Abstract

1,2,4-Trimethoxybenzene (ZY16) is a natural compound identified as a selective nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome inhibitor. Studies have shown that NLRP3 inflammasome activation contributes significantly to the pathogenesis of diabetic cognitive impairment (DCD). Using a rat model of DCD induced by a high-carbohydrate and high-fat diet combined with streptozotocin (STZ), we evaluated the therapeutic effects of ZY16 and metformin on cognitive impairment in diabetic rats through the following measures: blood glucose levels, behavioral tests, biodiversity analysis of gut microbiota, and molecular and histological analyses. The results showed that ZY16 significantly reduced the area under the curve (AUC) of oral glucose tolerance and reduced glycated serum protein (GSP), Insulin, and Insulin resistance (IR) levels. It also ameliorated diabetes-related hyperlipidemia, lowered malondialdehyde (MDA) levels, and alleviated oxidative stress. In addition, it enhanced learning and memory abilities and improved neuropathy. Furthermore, ZY16 reduced the expression of NLRP3, apoptosis-associated speck-like protein (ASC), Gasdermin D (GSDMD), and Caspase-1. In addition, ZY16 reduced the levels of inflammatory factors such as Interleukin-1 beta (IL-1β), Interleukin-18 (IL-18) and Tumor necrosis factor-alpha (TNF-α) in the hippocampus of rats. Species richness, diversity, and composition of the rat gut microbiota was recovered. In conclusion, ZY16 plays a beneficial role in DCD by inhibiting NLRP3 inflammasome formation and restoring intestinal flora. This finding may contribute to the development of a novel intervention for the clinical management of DCD.

Keywords

1,2,4-Trimethoxybenzene; Diabetic cognitive dysfunction; Gut microbiota; NLRP3 inflammasome; Type 2 diabetes mellitus.

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