Yao Yue, Shu Ting, Guo Xiying, Huang Jing, Chen Qingjie, Liu Xiufen, Ouyang Changhan, Yang Xiaosong, Lei Min
Pharmacy College, Xianning Medical College, Hubei University of Science and Technology, No. 88, Xianning Avenue, Xianning City, Hubei Province 437100, China.
The People's Hospital of Lezhi, No. 405, Yingbin Avenue, Lezhi County, Sichuan Province 641599, China.
ACS Omega. 2025 Apr 11;10(15):15673-15680. doi: 10.1021/acsomega.5c00535. eCollection 2025 Apr 22.
Examining how hypoglycemic medications affect brain function is one of the best approaches to addressing cognitive impairment. In this study, trelagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, was utilized to assess memory loss in diabetic rats through fear conditioning tests. Trelagliptin restored fear memory in diabetic rats that had been disrupted over a relatively long period (24 h) or extended period (5 days). Moreover, trelagliptin treatment reduced the higher incidence of neuronal cell death in the cerebral cortex, as observed via Nissl or hematoxylin and eosin staining. Subsequent analyses revealed that diabetic rats exhibited elevated levels of inflammatory cytokines (p-IKKα and p-NFκB) and a trend toward oxidative damage, indicated by malondialdehyde (MDA), superoxide dismutase 2 (SOD2), and glutathione peroxidase 4 (GPX4) detection. However, administration of trelagliptin reversed these markers to baseline levels. Additionally, trelagliptin activated p-AMPK, p-AKT, and p-GSK-3β. Notably, trelagliptin upregulated the expression of postsynaptic density protein 95 (PSD95) and synaptotagmin 1 (SYT1) while downregulating amyloid precursor protein (APP) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). These findings suggest that trelagliptin alleviates cognitive impairment in diabetic rats, likely through AMPK-AKT-GSK-3β-mediated mitigation of oxidative stress, enhancement of synaptic plasticity, and reduction of Aβ accumulation.
研究降糖药物如何影响脑功能是解决认知障碍的最佳方法之一。在本研究中，二肽基肽酶-4（DPP4）抑制剂曲格列汀被用于通过恐惧条件反射试验评估糖尿病大鼠的记忆丧失情况。曲格列汀恢复了在相对较长时间（24小时）或延长时间（5天）内被破坏的糖尿病大鼠的恐惧记忆。此外，通过尼氏染色或苏木精-伊红染色观察发现，曲格列汀治疗降低了大脑皮质中神经元细胞死亡的较高发生率。后续分析显示，糖尿病大鼠表现出炎症细胞因子（p-IKKα和p-NFκB）水平升高以及氧化损伤趋势，这通过丙二醛（MDA）、超氧化物歧化酶2（SOD2）和谷胱甘肽过氧化物酶4（GPX4）检测得以表明。然而，给予曲格列汀可将这些标志物逆转至基线水平。此外，曲格列汀激活了p-AMPK、p-AKT和p-GSK-3β。值得注意的是，曲格列汀上调了突触后致密蛋白95（PSD95）和突触结合蛋白1（SYT1）的表达，同时下调了淀粉样前体蛋白（APP）和β-位点淀粉样前体蛋白裂解酶1（BACE1）。这些发现表明，曲格列汀可能通过AMPK-AKT-GSK-3β介导的减轻氧化应激、增强突触可塑性和减少Aβ积累来减轻糖尿病大鼠的认知障碍。
