Studies have shown that diabetes is associated with the occurrence of neurodegenerative diseases and cognitive decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The superior efficacy of liraglutide (LIRA) for cognitive impairment and numerous neurodegenerative diseases has been widely demonstrated. This study determined the effects of LIRA on diabetic cognitive impairment and on the levels of oxidative stress, lipid peroxidation, iron metabolism and ferroptosis in the hippocampus. Mice were injected daily with liraglutide (200 μg/kg/d) for 5 weeks. LIRA could repair damaged neurons and synapses, and it increased the protein expression levels of PSD 95, SYN, and BDNF. Furthermore, LIRA significantly decreased oxidative stress and lipid peroxidation levels by downregulating the production of ROS and MDA and upregulating SOD and GSH-Px in the serum and hippocampus, and the upregulation of SOD2 expression was also proven. The decreased levels of TfR1 and the upregulation of FPN1 and FTH proteins observed in the LIRA-treated db/db group were shown to reduce iron overload in the hippocampus, whereas the increased expression of Mtft and decreased expression of Mfrn in the mitochondria indicated that mitochondrial iron overload was ameliorated. Finally, LIRA was shown to prevent ferroptosis in the hippocampus by elevating the expression of GPX4 and SLC7A11 and suppressing the excessive amount of ACSL4; simultaneously, the damage to the mitochondria observed by TEM was also repaired. For the first time, we proved in the T2DM model that ferroptosis occurs in the hippocampus, which may play a role in diabetic cognitive impairment. LIRA can reduce oxidative stress, lipid peroxidation and iron overload in diabetic cognitive disorders and further inhibit ferroptosis, thereby weakening the damage to hippocampal neurons and synaptic plasticity and ultimately restoring cognitive function.

研究表明，糖尿病与神经退行性疾病的发生和认知能力下降有关。然而，目前还没有针对糖尿病引起的认知功能障碍的有效治疗方法。利拉鲁肽 (LIRA) 对认知障碍和多种神经退行性疾病的卓越疗效已得到广泛证实。本研究确定了 LIRA 对糖尿病认知障碍和海马氧化应激、脂质过氧化、铁代谢和铁死亡水平的影响。每天给小鼠注射利拉鲁肽 (200 μg/kg/d)，持续 5 周。LIRA 可以修复受损的神经元和突触，并增加 PSD 95、SYN 和 BDNF 的蛋白质表达水平。此外，LIRA 通过下调 ROS 和 MDA 的产生以及上调血清和海马中的 SOD 和 GSH-Px 显着降低氧化应激和脂质过氧化水平，并且还证明了 SOD2 表达的上调。在 LIRA 处理的 db/db 组中观察到的 TfR1 水平降低以及 FPN1 和 FTH 蛋白的上调显示减少了海马中的铁过载，而线粒体中 Mtft 的表达增加和 Mfrn 的表达减少表明线粒体铁过载得到改善。最后，LIRA 被证明可以通过提高 GPX4 和 SLC7A11 的表达和抑制过量的 ACSL4 来预防海马铁死亡；同时，TEM观察到的线粒体损伤也得到修复。首次，我们在 T2DM 模型中证明，铁死亡发生在海马区，这可能在糖尿病认知障碍中起作用。LIRA可以降低糖尿病认知障碍中的氧化应激、脂质过氧化和铁过载，进一步抑制铁死亡，从而减弱海马神经元和突触可塑性的损伤，最终恢复认知功能。