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

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.