Resveratrol Prevents Cognitive Impairment in Type 2 Diabetic Mice by Upregulating Nrf2 Expression and Transcriptional Level

Xiaoxiao Wang; Hui Fang; Gang Xu; Ying Yang; Ruizhe Xu; Qiang Liu; Xiangyu Xue; Jiaqi Liu; Hezhi Wang

doi:10.2147/DMSO.S243560

Resveratrol Prevents Cognitive Impairment in Type 2 Diabetic Mice by Upregulating Nrf2 Expression and Transcriptional Level

Diabetes Metab Syndr Obes. 2020 Apr 7:13:1061-1075. doi: 10.2147/DMSO.S243560. eCollection 2020.

Authors

Xiaoxiao Wang¹, Hui Fang², Gang Xu³, Ying Yang², Ruizhe Xu⁴, Qiang Liu⁵, Xiangyu Xue⁵, Jiaqi Liu⁵, Hezhi Wang⁶

Affiliations

¹ Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, People's Republic of China.
² Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, People's Republic of China.
³ Department of Burns and Orthopedics, Tangshan Gongren Hospital, Tangshan, Hebei 063000, People's Republic of China.
⁴ Department of Clinical Medicine, Tangshan Vocational and Technical College, Tangshan, Hebei, 063000, People's Republic of China.
⁵ Department of Internal Medicine, North China University of Science and Technology, Tangshan, Hebei 063000, People's Republic of China.
⁶ Department of Surgery, Hebei Medical University, Shijiazhuang 050017, People's Republic of China.

Abstract

Purpose: This study aimed to determine whether the natural antioxidant resveratrol (RSV) prevents type 2 diabetes mellitus (T2DM)-induced cognitive impairment and to explore whether redox-associated factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the neuroprotective effect of RSV.

Materials and methods: We established a T2DM model with 8-week-old male ICR mice by administration of a high-fat diet for 2 months and low-dose streptozotocin for 3 days. Then, diabetic and age-matched control mice were treated with or without RSV for 4 months every other day and subjected to the Morris water maze test. After the mice were euthanized, whole brains were sectioned for Nissl staining and immunofluorescence labeling. Hippocampal sections were observed by transmission electron microscopy to evaluate the ultrastructure of synapses. Inflammatory factors, oxidative stress-related indexes, and Nrf2 and downstream target gene expression were analyzed in hippocampal tissues by quantitative real-time PCR, Western blotting, and associated quantitative kits.

Results: In the Morris water maze test, compared to control mice, T2DM mice showed learning and memory impairments, but RSV treatment prevented the learning and memory decline in T2DM mice. Similarly, RSV prevented T2DM-induced hippocampal neuron destruction and synaptic ultrastructural damage. The expression levels of inflammatory factors and oxidative stress-related indicators were increased in the T2DM group compared with the control group but were decreased significantly by RSV treatment in the T2DM group. Additionally, the expression of Nrf2 and its downstream target genes was decreased in the T2DM group compared with the control group and was significantly increased by RSV treatment in the T2DM group.

Conclusion: RSV prevented T2DM-induced cognitive impairment through anti-inflammatory and antioxidant activities. This effect was accompanied by the upregulation of Nrf2 transcriptional activity and the increased expression of downstream antioxidant genes.

Keywords: Nrf2 activator; inflammation; natural antioxidant; oxidative stress.