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

Abstract

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.

Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

“… 37 According to one report, SGLT2/SLC5A2 was detected in the hypothalamus, amygdala, periaqueductal gray, and the nucleus of the solitary tract by immunohistochemical analysis. 12 Another report showed that SGLT2/SLC5A2 is present in ependymal cells and choroid plexus epithelial cells. 11 Thus, there is still no consensus regarding which CNS locations express SGLT2/SLC5A2.…”

“…This assumption is consistent with the sites previously suggested to harbor SGLT2/SLC5A2. 12 Another possibility is that spinal fluid flows from the LV to the lower ventricles, and the SGLT2 inhibitor thereby reaches more SGLT2-expressing ependymal cells expressed around the cerebral ventricle, which may explain why the effect is stronger in the upper ventricles.…”

“… 40 41 Oral administration of SGLT2 inhibitors has been reported to enhance c-fos expression in the PVH, ARC, and LH, consistent with our observations. 12 AMPK is known to be the main sensor of cellular energy status, and coordinates metabolism at the whole-body level. 42 In the hypothalamus, regulation of AMPK phosphorylation is a mechanism for detecting nutritional changes.…”

“… 11 Another recent report showed that SGLT2/SLC5A2 is present in the forebrains and brain stems of mice. 12 One study suggests that glucose uptake occurs via SGLT2/SLC5A2 in the rat brain. 13 To date, expression of SGLT2/SLC5A2 in the rat brain has not been unequivocally proven, and its function in the CNS thus remains uncertain.…”

SGLT2 Inhibitor-Induced Sympathoexcitation in White Adipose Tissue: A Novel Mechanism for Beiging

“…In the context of the parasympathetic nervous system, its activation acts to dampen the SNS and subsequently dull the “fight or flight” response. Recently, Dapagliflozin has been found to regulate cardiovascular activity by increasing the activity of the parasympathetic nervous system in C57Bl/6 mice [ 25 ]. It is well known that the increased activity of the parasympathetic nervous system is associated with increased tyrosine hydroxylase expression [ 26 , 27 ].…”