Compound Danshen Dripping Pills moderate intestinal flora and the TLR4/MyD88/NF-κB signaling pathway in alleviating cognitive dysfunction in type 2 diabetic KK-Ay mice

Xunjie Fan; Yuanyuan Zhang; Yi Song; Yanyan Zhao; Yanan Xu; Feng Guo; Mingwei Shao; Xiaojun Ma; Wei Zhang; Fangyi Wei; Guijun Qin

doi:10.1016/j.phymed.2023.154656

Compound Danshen Dripping Pills moderate intestinal flora and the TLR4/MyD88/NF-κB signaling pathway in alleviating cognitive dysfunction in type 2 diabetic KK-Ay mice

Phytomedicine. 2023 Mar:111:154656. doi: 10.1016/j.phymed.2023.154656. Epub 2023 Jan 10.

Authors

Xunjie Fan¹, Yuanyuan Zhang², Yi Song¹, Yanyan Zhao², Yanan Xu¹, Feng Guo¹, Mingwei Shao¹, Xiaojun Ma², Wei Zhang², Fangyi Wei¹, Guijun Qin³

Affiliations

¹ Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Rd., Zhengzhou, Henan 450052, China; Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China.
² Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Rd., Zhengzhou, Henan 450052, China.
³ Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Rd., Zhengzhou, Henan 450052, China. Electronic address: hyqingj@zzu.edu.cn.

PMID: 36682300
DOI: 10.1016/j.phymed.2023.154656

Abstract

Backgroud: Bidirectional communications between the gut microbiota and the brain may play a critical role in diabetes-related cognitive impairment. Compound Danshen Dripping Pills (CDDP) treatment has shown remarkable improvement in cognitive impairment in people with type 2 diabetes mellitus (T2DM) in clinical settings, but the underlying mechanisms remain unknown.

Purpose: An extensive detailed strategy via in vivo functional experiments, transcriptomics, metabolomics, and network pharmacology was adopted to investigate the CDDP-treatment mechanism in diabetic cognitive dysfunction.

Methods: For 12 weeks, KK-Ay mice, a spontaneous T2DM model, were intragastrically administered various doses of CDDP solution or an equivalent volume of water, and the nootropic drug piracetam was orally administered as a positive control. At the 12th week, cognition was assessed using Morris water maze tests and brain magnetic resonance imaging (MRI). Furthermore, transcriptomics, metabolomics, and network pharmacology analyses were applied to reveal novel molecular mechanisms of CDDP-treatment in diabetic cognitive dysfunction of KK-Ay mice, which were then validated using quantitative real-time polymerase chain reaction and Western blot.

Results: Here we verified that CDDP can suppress inflammatory response and alleviate the cognitive dysfunction in KK-Ay mice. Also, as demonstrated by 16S rRNA sequencing and short-chain fatty acids (SCFAs) analysis, CDDP attenuated intestinal flora disorder as well as increases of metabolites including butyric acid, hexanoic acid, and isohexic acid. Given the integrated analyses of network pharmacology, transcriptomic, metabolomic data, and molecular biology, the TLR4/MyD88/NF-κB signaling pathway was activated in diabetes, which could be reversed by CDDP.

Conclusions: Our findings demonstrate that CDDP restructures the gut microbiota composition and increased the intestinal SCFAs in KK-Ay mice, which might inhibit neuroinflammation, and thus improve diabetic mice cognitive disorder.

Keywords: Cognitive dysfunction; Compound Danshen dripping pills; Intestinal flora; KK-Ay mice; Type 2 diabetes mellitus.

MeSH terms

Animals
Cognitive Dysfunction* / drug therapy
Diabetes Mellitus, Experimental* / drug therapy
Diabetes Mellitus, Experimental* / metabolism
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / metabolism
Drugs, Chinese Herbal* / pharmacology
Drugs, Chinese Herbal* / therapeutic use
Gastrointestinal Microbiome*
Mice
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / metabolism
RNA, Ribosomal, 16S
Signal Transduction
Toll-Like Receptor 4 / metabolism

Substances

NF-kappa B
Myeloid Differentiation Factor 88
Toll-Like Receptor 4
RNA, Ribosomal, 16S
Drugs, Chinese Herbal
Myd88 protein, mouse
Tlr4 protein, mouse