Basic Study
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World J Psychiatry. Mar 19, 2022; 12(3): 410-424
Published online Mar 19, 2022. doi: 10.5498/wjp.v12.i3.410
Magnesium-L-threonate exhibited a neuroprotective effect against oxidative stress damage in HT22 cells and Alzheimer’s disease mouse model
Ying Xiong, Yu-Ting Ruan, Jing Zhao, Yu-Wen Yang, Li-Ping Chen, Ying-Ren Mai, Qun Yu, Zhi-Yu Cao, Fei-Fei Liu, Wang Liao, Jun Liu
Ying Xiong, Ying-Ren Mai, Qun Yu, Zhi-Yu Cao, Jun Liu, Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
Yu-Ting Ruan, Department of Rehabilitation Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
Jing Zhao, Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
Yu-Wen Yang, Li-Ping Chen, Department of Medical Ultrasound, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, Guangdong Province, China
Fei-Fei Liu, Department of Medical Ultrasound, Xiang’an Hospital of Xiamen University, Xiamen 361000, Fujian Province, China
Wang Liao, Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
Author contributions: Xiong Y and Ruan YT contributed to designing this study, collecting samples, carrying out experiments and writing the manuscript; Zhao J, Yang YW, Chen LP and Mai YR contributed to collecting samples and revising the manuscript; Yu Q, Cao ZY, Liu FF and Liao W contributed to analyzing the data and revising the manuscript; Liu J had full access to all of the data in the study, and took responsibility for the integrity of the data and the accuracy of the data analysis; all authors have approved the final article.
Supported by National Natural Science Foundation of China, No. 81870836; Natural Science Foundation of Guangdong Province, China, No. 2020A1515010210; Science and Technology Program of Guangzhou, China, No. 202007030010; and Guangdong Basic and Applied Basic Research Foundation, China, No. 2020A1515110317 and No. 2021A1515010705.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC), Sun Yat-sen University (Approval No. SYSU-IACUC-2019-000005).
Conflict-of-interest statement: All authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
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: Jun Liu, MD, Professor, Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou 510120, Guangdong Province, China. liujun6@mail.sysu.edu.cn
Received: October 11, 2021
Peer-review started: October 11, 2021
First decision: November 17, 2021
Revised: December 15, 2021
Accepted: March 6, 2022
Article in press: March 6, 2022
Published online: March 19, 2022
Processing time: 158 Days and 1.8 Hours
Abstract
BACKGROUND

Oxidative stress results in the production of excess reactive oxygen species (ROS) and triggers hippocampal neuronal damage as well as occupies a key role in the pathological mechanisms of neurodegenerative disorders such as Alzheimer’s disease (AD). A recent study confirmed that magnesium had an inhibitory effect against oxidative stress-related malondialdehyde in vitro. However, whether Magnesium-L-threonate (MgT) is capable of suppressing oxidative stress damage in amyloid β (Aβ)25-35-treated HT22 cells and the AD mouse model still remains to be investigated.

AIM

To explore the neuroprotective effect of MgT against oxidative stress injury in vitro and in vivo, and investigate the mechanism.

METHODS

Aβ25-35-induced HT22 cells were preconditioned with MgT for 12 h. APPswe/PS1dE9 (APP/PS1) mice were orally administered with MgT daily for 3 mo. After MgT treatment, the viability of Aβ25-35-treated HT22 cells was determined via conducting cell counting kit-8 test and the cognition of APP/PS1 mice was measured through the Morris Water Maze. Flow cytometry experiments were applied to assess the ROS levels of HT22 cells and measure the apoptosis rate of HT22 cells or hippocampal neurons. Expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), hypoxia-inducible factor (HIF)-1α, NADPH oxidase (NOX) 4, Aβ1-42 and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway proteins was quantified by Western blot.

RESULTS

In vitro data confirmed that Aβ25–35-induced HT22 cells had a significantly lower cell viability, higher ROS level and higher apoptosis rates compared with those of control cells (all P < 0.001). MgT prevented the Aβ25-35-triggered oxidative stress damage by elevating viability and decreasing ROS formation and apoptosis of HT22 cells (all P < 0.001). APP/PS1 mice exhibited worse cognitive performance and higher apoptosis rate of hippocampal neurons than wild-type (WT) mice (all P < 0.01). Meanwhile, significant higher expression of Aβ1-42 and NOX4 proteins was detected in APP/PS1 mice than those of WT mice (both P < 0.01). MgT also ameliorated the cognitive deficit, suppressed the apoptosis of hippocampal neuron and downregulated the expression of Aβ1-42 and NOX4 proteins in APP/PS1 mouse (all P < 0.05). Moreover, MgT intervention significantly downregulated HIF-1α and Bax, upregulated Bcl-2 and activated the PI3K/Akt pathway both in vitro and in vivo (all P < 0.05).

CONCLUSION

MgT exhibits neuroprotective effects against oxidative stress and hippocampal neuronal apoptosis in Aβ25-35-treated HT22 cells and APP/PS1 mice.

Keywords: Alzheimer’s disease; Magnesium; Neuroprotective effect; Oxidative stress; Hippocampal; Neuronal apoptosis

Core Tip: The dysfunction of oxidative stress is considered to stimulate the production of reactive oxygen species and induce hippocampal neuron damage which are the significant hallmarks of neurodegenerative diseases such as Alzheimer’s disease. Recent studies have explored the in vitro anti-malondialdehyde effect of magnesium. However, the potential neuroprotective effect of Magnesium-L-threonate (MgT) against oxidative stress remains to be explored. Our study demonstrated that MgT exhibited neuroprotective effects on suppressing oxidative stress and hippocampal neuronal apoptosis in vitro and in vivo, suggesting the promising therapeutic potential of MgT in oxidative stress-associated neurodegenerative disorders.