Zheng XZ, Yu HY, Chen YR, Fang JS. Aucubin mitigates the elevation of microglial aerobic glycolysis and inflammation in diabetic neuropathic pain via aldose reductase. World J Diabetes 2025; 16(5): 103915 [DOI: 10.4239/wjd.v16.i5.103915]
Corresponding Author of This Article
Xue-Zhen Zheng, MD, Department of Anesthesiology, The First People's Hospital of Chun'an County, No. 1869 Huanhu North Road, Qiandaohu Town, Chun'an County, Hangzhou 311700, Zhejiang Province, China. zhengxuezhen2024@163.com
Research Domain of This Article
Pharmacology & Pharmacy
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xue-Zhen Zheng, Hong-Yan Yu, Jian-Sheng Fang, Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
Ye-Ru Chen, Department of Anaesthesiology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou 310058, Zhejiang Province, China
Co-corresponding authors: Xue-Zhen Zheng and Jian-Sheng Fang.
Author contributions: Zheng XZ and Fang JS designed the study; Zheng XZ and Yu HY prepared the samples, performed the experiments, and analyzed the data; Chen YR and Fang JS wrote the original manuscript; all authors read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82001424.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Zhejiang University Experimental Animal Ethics Committee Institutional Review Board (Approval No. ZJU20240012).
Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data generated in the present study may be requested from the corresponding author. The data generated in the present study are included in the figures and/or tables of this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xue-Zhen Zheng, MD, Department of Anesthesiology, The First People's Hospital of Chun'an County, No. 1869 Huanhu North Road, Qiandaohu Town, Chun'an County, Hangzhou 311700, Zhejiang Province, China. zhengxuezhen2024@163.com
Received: December 4, 2024 Revised: January 26, 2025 Accepted: February 24, 2025 Published online: May 15, 2025 Processing time: 142 Days and 0.6 Hours
Abstract
BACKGROUND
Treatment of diabetic neuropathy is often limited by side effects. Aucubin, an iridoid glycoside derived from natural plants, exhibits notable anti-inflammatory and antioxidant properties.
AIM
To investigate the effects of aucubin on diabetic neuropathic pain (DNP) and glycolysis and inflammation in microglia.
METHODS
Streptozotocin (STZ) was used to establish a DNP animal model. Blood glucose levels and body weight of mice were measured following STZ administration. Paw withdrawal threshold was calculated for mechanical allodynia. Paw withdrawal latency was recorded for thermal hyperalgesia. The open field test and elevated plus maze was used to assess locomotor activity and anxiety-like behavior. Western blotting was utilized for analysis of protein expression. Immunofluorescence staining was measured for morphometric analysis of microglia. Glycolysis and ATP synthesis in BV-2 cell lines were detected by metabolic extracellular flux analysis. The SwissTargetPrediction and STRING databases were used for comprehensive screening to identify potential target proteins for aucubin. The molecular docking between the possible target proteins and aucubin was investigated using Auto Dock Tool. The BV-2 cell line was transfected with lentiviral AKR1B1-shRNA to further ascertain the function of AKR1B1 in the impact of aucubin on aerobic glycolysis and inflammation during high glucose stimulation.
RESULTS
Aucubin significantly improved pain and anxiety-like behavior in STZ-induced diabetic mice and restored microglial aerobic glycolysis and inflammation. Several public databases and molecular docking studies suggested that AKR1B1, MMP2 and MMP9 are involved in the effect of aucubin on DNP. Aucubin failed to restore aerobic glycolysis and inflammation in the context of AKR1B1 deficiency.
CONCLUSION
Aucubin has potential as a therapeutic agent for alleviating DNP by inhibiting expression of AKR1B1.
Core Tip: Our research demonstrates that aucubin markedly reduces pain and anxiety-like behavior in Streptozotocin-induced diabetic mice. Furthermore, aucubin reinstates microglial aerobic glycolysis and mitigates inflammation. Utilizing the SwissTargetPrediction database, we discovered 22 prospective protein targets for aucubin concerning diabetic neuropathic pain (DNP). Analysis of protein-protein interaction networks and molecular docking experiments identified the potential role of aldose reductase (AKR1B1) to streptozotocin therapy. Aucubin does not repair aerobic glycolysis and inflammation in the setting of AKR1B1 depletion. The findings indicate that aucubin could be a potential therapeutic drug for DNP, with AKR1B1 identified as a major target.
