Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050000, China.
Department of Orthopedics, Handan First Hospital, Handan 056000, China.
Brain Res. 2025 Jan 1;1846:149241. doi: 10.1016/j.brainres.2024.149241. Epub 2024 Sep 14.
This study aimed to reveal the role of fingolimod (FTY720) in mice with type 2 diabetes-associated cognitive decline and explore its potential neuroprotective mechanism. Mice were divided into five groups: normal control, normal control + FTY720 (1.0 mg/kg/day), type 2 diabetes mellitus, type 2 diabetes mellitus + low-dose FTY720 (0.5 mg/kg/day), and type 2 diabetes mellitus + high-dose FTY720 (1.0 mg/kg/day). Different doses of FTY720 were administered daily for 8 weeks after the induction of type 2 diabetes using a four-week high-fat diet feeding combined with continuous low-dose intraperitoneal injections of streptozotocin. After 8 weeks of treatment, the body weights and fasting blood glucose levels of mice from the five groups were compared. Morris water maze and new object recognition tests were used to evaluate cognitive function. Pathological changes in the hippocampal CA1 region were observed using haematoxylin-eosin and Nissl staining, and the ultrastructure of the hippocampal neurones was assessed using transmission electron microscopy. The expression levels of autophagy- and apoptosis-related proteins, such as LC3, Beclin-1, P62, Bax, and Bcl-2, in the mice hippocampus were detected by western blotting. Simultaneously, AMPK/mTOR signaling pathway proteins were detected to understand the potential mechanism. FTY720 had no significant effect on the body weight or fasting blood glucose levels in mice with type 2 diabetes. However, both FTY720 doses improved the cognitive function and hippocampal damage. In addition, the results suggested that FTY720 dramatically decreased P62 and Bax levels and increased LC3 II/LC3 I ratio, Beclin-1, and Bcl-2 expression in the hippocampus of type 2 diabetic mice. FTY720 also affected the expression of the AMPK/mTOR signaling pathway. Thus, FTY720 improved cognitive function and hippocampal pathological changes in type 2 diabetic mice without affecting fasting blood glucose levels. Our results show that FTY720 may exert neuroprotective effects in vivo by enhancing hippocampal autophagy and inhibiting apoptosis via the AMPK/mTOR signaling pathway.
本研究旨在揭示芬戈莫德（FTY720）在 2 型糖尿病相关认知衰退小鼠中的作用，并探讨其潜在的神经保护机制。将小鼠分为五组：正常对照组、正常对照组+FTY720（1.0mg/kg/天）、2 型糖尿病组、2 型糖尿病+低剂量 FTY720（0.5mg/kg/天）和 2 型糖尿病+高剂量 FTY720（1.0mg/kg/天）。用高脂饮食喂养 4 周，同时连续腹腔注射小剂量链脲佐菌素诱导 2 型糖尿病后，每天给予不同剂量的 FTY720 治疗 8 周。治疗 8 周后，比较五组小鼠的体重和空腹血糖水平。采用 Morris 水迷宫和新物体识别试验评估认知功能。用苏木精-伊红和尼氏染色观察海马 CA1 区的病理变化，用透射电镜观察海马神经元的超微结构。采用 Western blot 检测小鼠海马自噬和凋亡相关蛋白 LC3、Beclin-1、P62、Bax 和 Bcl-2 的表达水平。同时，检测 AMPK/mTOR 信号通路蛋白，以了解潜在的机制。FTY720 对 2 型糖尿病小鼠的体重或空腹血糖水平无显著影响。然而，两种 FTY720 剂量均改善了认知功能和海马损伤。此外，结果表明 FTY720 可显著降低 2 型糖尿病小鼠海马组织中 P62 和 Bax 水平，增加 LC3 II/LC3 I 比值、Beclin-1 和 Bcl-2 表达。FTY720 还影响 AMPK/mTOR 信号通路的表达。因此，FTY720 改善了 2 型糖尿病小鼠的认知功能和海马病理变化，而不影响空腹血糖水平。我们的研究结果表明，FTY720 通过增强海马自噬和抑制凋亡，可能通过 AMPK/mTOR 信号通路发挥体内神经保护作用。
