Improvement of actin dynamics and cognitive impairment in diabetes through troxerutin-mediated downregulation of TRPM7/CaN/cofilin

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2023-09-28 DOI:10.1016/j.npep.2023.102381

Hongyan Li , Jie Li , Pin Wang , Fang Yuan , Songyun Zhang

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Abstract

Diabetic cognitive impairment is a central nervous complication of diabetes mellitus. Its specific pathogenesis is unknown, and no effective treatment strategy is currently available. An imbalance in actin dynamics is an important mechanism underlying cognitive impairment. Transient receptor potential channel 7 (TRPM7) mediates actin dynamics imbalance through calcineurin (CaN) and cofilin cascades involved in various neurodegenerative diseases. We previously demonstrated that TRPM7 expression is increased in diabetic cognitive impairment, and troxerutin has been shown to ameliorate diabetic cognitive impairment. However, the relationship between troxerutin and TRPM7 remains unclear. In this study, we hypothesize that troxerutin may improve diabetic cognitive impairment by enhancing actin dynamics through downregulation of the TRPM7/CaN/cofilin pathway. To test this hypothesis, we divided db/m and db/db mice into the following groups: normal control group (NC), normal + troxerutin group (NT), diabetic group (DM), diabetic + troxerutin group (DT) and diabetic + troxerutin + bradykinin group (DTB). The results showed that diabetic mice exhibited cognitive impairment at 17 weeks of age, TRPM7, CaN, cofilin and G-actin were highly expressed in the CA1 region of hippocampus, while p-cofilin and F-actin expression decreased. Furthermore, hippocampal neuronal cellsshowed varying degrees of damage. The length of synaptic active zone, the width of synaptic cleft, and the number of synapses per high-power field were decreased. Troxerutin intervention alleviated these manifestations in the DT group; however, the effect of troxerutin was weakened in the DTB group. In conclusion, our findings suggest that diabetes leads to cognitive impairment, activation of the TRPM7/CaN/cofilin pathway, actin dynamics imbalance, and destruction of hippocampal neuronal cells and synapses. Troxerutin can downregulate TRPM7/CaN/cofilin, improve actin dynamics imbalance, and ameliorate cognitive impairment in diabetic mice. This study provides a new avenue for exploring and treating cognitive impairment in diabetes.

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通过曲克芦丁介导的TRPM7/CaN/cofilin下调改善糖尿病患者的肌动蛋白动力学和认知障碍。

糖尿病认知障碍是糖尿病的一种中枢神经并发症。其具体发病机制尚不清楚，目前尚无有效的治疗策略。肌动蛋白动力学失衡是认知障碍的重要机制。瞬时受体电位通道7（TRPM7）通过参与各种神经退行性疾病的钙调神经磷酸酶（CaN）和辅纤维蛋白级联介导肌动蛋白动力学失衡。我们之前已经证明，TRPM7的表达在糖尿病认知障碍中增加，曲克芦丁已被证明可以改善糖尿病认知障碍。然而，曲克芦丁和TRPM7之间的关系尚不清楚。在这项研究中，我们假设曲克芦丁可能通过下调TRPM7/CaN/cofilin途径增强肌动蛋白动力学来改善糖尿病认知障碍。为了验证这一假设，我们将db/m和db/db小鼠分为以下组：正常对照组（NC）、正常+曲克芦丁组（NT）、糖尿病组（DM）、糖尿病+曲克rutin组（DT）和糖尿病+曲克rutin+缓激肽组（DTB）。结果表明，糖尿病小鼠在17周龄时表现出认知障碍，TRPM7、CaN、cofilin和G-actin在海马CA1区高表达，而p-cofilin、F-actin表达下降。此外，海马神经元细胞表现出不同程度的损伤。突触活动区的长度、突触间隙的宽度和每个高功率场的突触数量都有所减少。曲克芦丁干预减轻了DT组的这些表现；然而，曲克芦丁的作用在DTB组中减弱。总之，我们的研究结果表明，糖尿病会导致认知障碍、TRPM7/CaN/cofilin通路的激活、肌动蛋白动力学失衡以及海马神经元细胞和突触的破坏。曲克芦丁可下调糖尿病小鼠TRPM7/can/cofilin，改善肌动蛋白动力学失衡，改善认知障碍。本研究为探索和治疗糖尿病认知障碍提供了一条新的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.