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Liraglutide Alleviates Cognitive Deficit in db/db Mice: Involvement in Oxidative Stress, Iron Overload, and Ferroptosis

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Abstract

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.

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Acknowledgements

We thank Prof. En-Sheng Ji and Prof. Ya-Shuo Zhao in Hebei University of Chinese Medicine for their technical support in western blot and immunofluorescence.

Funding

This work was supported by the National Leading Talents Support Program of Chinese Medicine- Qihuang Scholar (Grant Number [2018]12); Liaoning **ngliao Talent Plan Project (Grant Number XLYC1807145); Liaoning University of Traditional Chinese Medicine Postdoctoral Research Fund (Grant Number 21601A2015).

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  1. Ji-Ren An and Jia-Nan Su have contributed equally to this work and share first authorship.

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  1. Liaoning University of Traditional Chinese Medicine, Huanggu District, No. 79, Mount Chong East Road, Shenyang, 110847, China

    Ji-Ren An, Jia-Nan Su, Gui-Yan Sun, Qing-Feng Wang, Nan Jiang, Yu-Feng Yang & Yan Shi

  2. Tian** University of Traditional Chinese Medicine, Tian**, 301617, China

    Ya-Dong Fan

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Contributions

J-RA, J-NS, Y-FY and YS carried out the experiments, analyzed the results, performed the experimental detection and wrote the manuscript. G-YS, Q-FW, Y-DF and NJ performed the animal models and part of the experimental detection.

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Correspondence to Yu-Feng Yang or Yan Shi.

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The animal research was approved by the Animal Experimental Ethics Committee of Liaoning University of Traditional Chinese Medicine (Ethics Approval Number: SYXK 2019–0004).

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An, JR., Su, JN., Sun, GY. et al. Liraglutide Alleviates Cognitive Deficit in db/db Mice: Involvement in Oxidative Stress, Iron Overload, and Ferroptosis. Neurochem Res 47, 279–294 (2022). https://doi.org/10.1007/s11064-021-03442-7

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