Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Aug 19, 2023; 13(8): 511-523
Published online Aug 19, 2023. doi: 10.5498/wjp.v13.i8.511
Dexmedetomidine mediates the mechanism of action of ferroptosis in mice with Alzheimer’s disease by regulating the mTOR-TFR1 pathway
Li Qiao, Gang Li, Hong-Xun Yuan
Li Qiao, Gang Li, Hong-Xun Yuan, Intensive Care Unit, Peking University International Hospital, Beijing 102206, China
Author contributions: Qiao L and Yuan HX conceived the study design and the content concept; Li G and Yuan HX performed data collection, extraction and analysis, interpreted and reviewed the data and drafts; Qiao L, Li G, and Yuan HX reviewed the final draft. Li G and Yuan HX are co-corresponding authors with equal contribution to the article.
Supported by Peking University International Hospital Foundation for Scientific Research, No. YN2022QN11.
Institutional animal care and use committee statement: All animal experiments were carried out after obtaining approval from the Experimental Animal Ethics Committee of Peking University International Hospital.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data for this study can be obtained from the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Gang Li, MBBS, Chief Physician, Intensive Care Unit, Peking University International Hospital, No. 1 Life Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China. ligang1@pkuih.edu.cn
Received: June 6, 2023
Peer-review started: June 6, 2023
First decision: June 21, 2023
Revised: July 6, 2023
Accepted: July 27, 2023
Article in press: July 27, 2023
Published online: August 19, 2023
Abstract
BACKGROUND

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and there are currently no effective drugs to delay progression of the disease. Ferroptosis may play a vital part in AD, and is therefore receiving increasing attention by researchers.

AIM

To investigate the effects of dexmedetomidine (Dex) on ferroptosis in AD mouse hippocampus.

METHODS

Hippocampal neurons (HNs) HT22 were induced by amyloid β-protein (Aβ) and both in vitro and in vivo AD mouse models were prepared via injections. The cell-counting kit-8 assay and immunofluorescence technique were adopted to determine cell proliferation activity and intracellular Fe2+ levels, and the TBA method and microplate method were employed for malondialdehyde and glutathione measurements, respectively. Hippocampal tissue damage was determined using hematoxylin and eosin and Nissl staining. Mouse learning and memory ability in each group was assessed by the Morris water maze test, and the expression levels of mammalian target of rapamycin (mTOR) signal molecules and ferroptosis-related proteins transferrin receptor 1 (TFR1), SLC7A11 and glutathione peroxidase 4 were examined by western blotting.

RESULTS

Dex enhanced lipid peroxidation and iron influx in mouse HNs in both in vitro and in vivo experiments, while inhibition of the mTOR axis blocked this process. These findings demonstrate that Dex can inhibit ferroptosis-induced damage in mouse HNs by activating mTOR-TFR1 signaling to regulate ferroptosis-associated proteins, thus alleviating cognitive dysfunction in AD mice.

CONCLUSION

Dex can activate the mTOR-TFR1 axis to inhibit ferroptosis in mouse HNs, thereby improving the learning and memory ability of mice.

Keywords: Dexmedetomidine, Ferroptosis, Alzheimer’s disease, Mammalian target of rapamycin, Mice

Core Tip: Iron death of nerve cells caused by iron overload is an important factor in various neurodegenerative diseases, including Alzheimer’s disease (AD). The classic mammalian target of rapamycin (mTOR) signaling pathway regulates the metabolism of iron ions by regulating transferrin receptor 1 (TFR1), thereby maintaining the intracellular iron balance. It has been shown that dexmedetomidine (Dex) inhibits the release of inflammatory factors and plays a neuroprotective role, thereby improving cognitive dysfunction in elderly rats. The Dex effectively improved hippocampal neuronal loss, cognitive dysfunction, learning and memory abilities in AD mice by regulating the mTOR-TFR1 signaling pathway to reduce iron death.