Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Mar 19, 2025; 15(3): 101178
Published online Mar 19, 2025. doi: 10.5498/wjp.v15.i3.101178
Inhibition of the microglial voltage-gated proton channel 1 channel ameliorates diabetes-associated cognitive dysfunction by regulating axon demyelination
Chun-Yu Li, Shu-Jun Zhang, Jia-Lu Xu, Yan Yang, Zhi-Xuan Zeng, De-Lin Ma
Chun-Yu Li, Shu-Jun Zhang, Jia-Lu Xu, Yan Yang, Zhi-Xuan Zeng, De-Lin Ma, Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Chun-Yu Li, Shu-Jun Zhang, Jia-Lu Xu, Yan Yang, Zhi-Xuan Zeng, De-Lin Ma, Hubei Clinical Medical Research Center for Endocrinology and Metabolic Diseases, Wuhan 430030, Hubei Province, China
Chun-Yu Li, Shu-Jun Zhang, Jia-Lu Xu, Yan Yang, Zhi-Xuan Zeng, De-Lin Ma, Branch of National Clinical Research Center for Metabolic Diseases, Wuhan 430030, Hubei Province, China
Co-corresponding authors: Zhi-Xuan Zeng and De-Lin Ma.
Author contributions: Li CY designed the study, performed data analysis, and drafted the manuscript; Zhang SJ and Xu JL conducted the majority of the experiments and contributed to data collection and interpretation; Yang Y participated in the statistical analysis and provided technical support for immunofluorescence and transmission electron microscopy experiments; Zeng ZX supervised the study, provided critical insights for experimental design, and assisted in manuscript revision; Ma DL coordinated the overall project, obtained funding, and approved the final manuscript as the corresponding author; All authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82300894.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: This study was approved by the Animal Ethics Committee of Tongji Medical College of Huazhong University of Science and Technology. Complying with the five freedoms (freedom from hunger and thirst, freedom from discomfort, freedom from pain, injury and disease, freedom to express normal behavior, freedom from fear and distress) and the 3Rs principle (replacement, reduction, refinement for experimental animals) (hence death is an unacceptable endpoint for experimental animals).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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: Data can be provided if necessary.
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: De-Lin Ma, Associate Chief Physician, PhD, Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. maderine4@163.com
Received: September 25, 2024
Revised: November 26, 2024
Accepted: December 27, 2024
Published online: March 19, 2025
Processing time: 153 Days and 21.5 Hours
Abstract
BACKGROUND

Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function, which is linked to oligodendrocyte dysfunction. The voltage-gated proton channel 1 (Hv1) is important for the cellular proton extrusion machinery. However, its role in regulating diabetes-induced cognitive dysfunction is unclear.

AIM

To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms, focusing on neuroinflammation, oligodendrocyte apoptosis, and axonal demyelination.

METHODS

A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice. Hv1 knockout (KO) and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence. Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination was analyzed using electron microscopy.

RESULTS

Hv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitive impairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, including interleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelin thickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.

CONCLUSION

Hv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelin integrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline and associated complications.

Keywords: Diabetes; Cognitive dysfunction; Voltage-gated proton channel 1; Neuroinflammation; Myelin regeneration

Core Tip: This study demonstrates that voltage-gated proton channel 1 (HV-1) knockout reduces neuroinflammation and alleviates axonal demyelination in diabetic mice, suggesting that HV-1 is a potential therapeutic target for treating diabetes-associated cognitive decline. The findings highlight the role of HV-1 in modulating microglial activity and promoting oligodendrocyte survival, which contributes to improved cognitive function in diabetic models. These insights offer new avenues for developing strategies to mitigate cognitive dysfunction related to diabetes by targeting HV-1.