TITLE:
Protective Effect of SGLT2 Inhibitor on D-Galactose-Induced Senescence in Mice and Its Mechanism
AUTHORS:
Zijun Ma, Meilin Xu, Kaiqin Jin, Guangfu Zhu, Xin Chen
KEYWORDS:
Aging, Neurodegenerative Diseases, SGLT2 Inhibitors, Oxidative Stress, SIRT1 Signalling Pathway
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.11 No.5,
May
24,
2023
ABSTRACT: Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice were divided into control group (13) and model group (53), and the model group was moulded by subcutaneous injection of D-galactose into the back of the neck, while the control group was treated with equal amount of saline for 8 weeks. The weight of each group of mice was observed and recorded every 7 days, and two groups of mice were randomly selected for frozen sections of brain tissue at the end of the modelling period to verify the aging model. 2. After the aging model was successfully established, the aging groups were divided into 5 groups: model group, dagliflozin-treated group (high and low dose), and dagliflozin + ex527-inhibited group (high and low dose). Fasting blood glucose was measured in each group every 2 weeks for 8 weeks. At the end of treatment, Morris water maze was performed at the end of the treatment. After execution of the mice, the organ indices of heart, brain, liver, kidney and spleen were measured; the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined. Results: After the successful establishment of the aging model, it was found that during the treatment phase of dagliflozin. 1) The organ indices of mice in the aging group were significantly lower than those of other groups, and no significant hypoglycemia was observed throughout the treatment process. 2) In the water maze test, mice in the aging group had a significantly longer latency in the plateau phase compared to the control and treatment groups, while the number of times the mice crossed the original plateau and the percentage of time spent exploring the original plateau quadrant were reduced after the plateau was removed. 3) The nerve cells in the aging mice were disorganized and the nuclei of the mice were deeply stained; the dagliflozin group improved the morphological changes in the brain of aging mice. 4) In addition, compared with the control mice, the serum MDA level was significantly increased and the antioxidant enzyme SOD activity was significantly decreased in the aging group, while compared with the aging group, dagliflozin significantly decreased the MDA level and increased the SOD activity. 5) The expression of SIRT1 and PGC-1α was significantly upregulated in the low and high doses of dagliflozin compared to the aging group. Conclusion: The present study suggests that dagliflozin can delay organ aging, improve the learning and memory ability of aging mice, and exert antioxidant effects, probably through upregulating the SIRT1/PGC-1α signaling pathway.