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.

糖尿病认知障碍是糖尿病的中枢神经并发症。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) 和肌动蛋白丝切蛋白级联介导肌动蛋白动力学失衡。我们之前证明TRPM7表达在糖尿病认知障碍中增加，并且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 之间的关系仍不清楚。在这项研究中，我们假设曲克芦丁可能通过下调 TRPM7/CaN/cofilin 通路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 + 曲克芦丁组（DT）和糖尿病组+曲克芦丁+缓激肽组(DTB)。结果显示，糖尿病小鼠在17周龄时出现认知障碍，海马CA1区TRPM7、CaN、cofilin和G-actin高表达，而p-cofilin和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倍视野的突触数量均减少。曲克芦丁干预缓解了 DT 组的这些症状；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。这项研究为探索和治疗糖尿病认知障碍提供了新途径。