Dapagliflozin improves diabetic cognitive impairment via indirectly modulating the mitochondria homeostasis of brain hippocampus in diabetic mice

Published: 23 February 2023| Version 1 | DOI: 10.17632/55ppzrk5hc.1
Contributor:
Qingjie Chen

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Background Cognitive impairment is increasingly recognized as an important comorbidity with diabetes progression. But the underlying molecular mechanism is not very clear. Dapagliflozin has been shown to promising effect on diabetes in rodent experiments and human clinical assays. This study aims to explore the effects of dapagliflozin on diabetic cognitive impairment and uncover the underlying mechanism. Methods: STZ-induced diabetic mice were utilized to construct diabetic cognitive impairment model in vivo. Dapagliflozin was administered to mice for 8 weeks via free drinking. Morris water maze test were used to evaluate the cognitive function of mice. Western blot were used to appraise protein expression. HE staining and Nissl staining were applied to observe the changes of morphological structure. Congo red staining was adopted for detecting Aβ/senile plaque formation. Mitochondrial morphology change was evaluated by transmission electron microscope, and the blood flow in the mouse cerebral cortex was appraised by Laser Doppler imaging assay individually. Results: After dapagliflozin treatment, compared with the Con group, the increased glycemic values and the downward body weight in the DM group were significant reversed by dapagliflozin. Behavioral assays showed that the spatial learning memory ability in diabetes mice were decrease. Fortunately, it was significantly improved after administrating with dapagliflozin. HE staining and Nissl staining showed that the number of neurons was reduced, disordered neurons were increased, the cell membrane edge was blurry and the Nissl bodies were difficult to identify in DM group, but remarkably relieved by dapagliflozin treatment. Meanwhile, increased Aβ/senile plaque and reduced cerebral blood flow in DM group was inhibited by dapagliflozin treatment. Moreover, the expressions of APP processing-related proteins and mitochondrial dynamic-related proteins in diabetic mouse hippocampus were rectified after dapagliflozin treatment. Incredibly, there was less SGLT2 in the hippocampus and cortex of diabetic mice than that of the Con group, but the SGLT2 inhibitor dapagliflozin increased significantly after several weeks of continuous administration. Conclusion: Diabetes-induced cognitive dysfunction was attenuated by dapagliflozin and the effect was indirect rather than direct. This may be the result of modulation of peripheral glycemic levels affecting the homeostasis of hippocampal mitochondria in diabetic mice.

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Hubei University Of Science and Technology

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