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Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice

Authors Nguyen T, Wen S, Gong M, Yuan X, Xu D, Wang C, Jin J, Zhou L

Received 28 April 2020

Accepted for publication 10 July 2020

Published 5 August 2020 Volume 2020:13 Pages 2781—2799

DOI https://doi.org/10.2147/DMSO.S258593

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 5

Editor who approved publication: Professor Ming-Hui Zou


Thiquynhnga Nguyen,* Song Wen,* Min Gong,* Xinlu Yuan, Dongxiang Xu, Chaoxun Wang, Jianlan Jin, Ligang Zhou

Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ligang Zhou
Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, People’s Republic of China
Tel +86 13611927616
Email zhouligang@yahoo.com

Purpose: This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity.
Material and Methods: Thirty-four normal male C57BL/6 mice were randomly assigned to 2 groups to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos, a neural activator. The distributional relationships of SGLT-2 and c-Fos were examined by immunofluorescence.
Results: Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin.
Conclusion: This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.

Keywords: sodium glucose co-transporter-2, dapagliflozin, c-Fos, cardiovascular activity, brain nuclei

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