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.
摘要：
糖尿病认知功能障碍是糖尿病的中枢神经并发症。其具体发病机制不明,目前尚无有效的治疗策略。肌动蛋白动力学的失衡是认知损害的重要机制。瞬时受体电位通道7（TRPM7）通过钙调磷酸酶（CaN）和cofilin级联参与各种神经退行性疾病介导肌动蛋白动力学失衡。我们先前证明，TRPM7表达在糖尿病性认知障碍中增加，和曲克鲁丁已被证明可以改善糖尿病性认知障碍。然而,曲克鲁丁与TRPM7之间的关系尚不清楚.在这项研究中,我们假设曲克鲁丁可能通过下调TRPM7/CaN/cofilin通路而增强肌动蛋白动力学,从而改善糖尿病性认知障碍.为了检验这个假设，将db/m和db/db小鼠分为正常对照组(NC),正常+曲克鲁丁组（NT），糖尿病组（DM），糖尿病+曲克芦丁组(DT)和糖尿病+曲克芦丁+缓激肽组(DTB)。结果显示，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和F-actin表达降低。此外，海马神经元细胞出现不同程度的损伤。突触活动区的长度，突触间隙的宽度,每个高功率场的突触数量减少。Troxerutin干预缓解了DT组的这些表现；然而，在DTB组中，曲克鲁丁的作用减弱。总之,我们的研究结果表明，糖尿病会导致认知障碍，激活TRPM7/CaN/cofilin途径，肌动蛋白动力学失衡，海马神经元细胞和突触的破坏。Troxerutin可以下调TRPM7/CaN/cofilin，改善肌动蛋白动力学失衡，并改善糖尿病小鼠的认知障碍。本研究为探索和治疗糖尿病认知障碍提供了新的途径。
