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

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

Abstract

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: brain nuclei; c-Fos; cardiovascular activity; dapagliflozin; sodium glucose co-transporter-2.

Conflict of interest statement

The drug tablets were provided by Astra Zeneca. The authors declare that they have no conflicts of interest for this work.

© 2020 Nguyen et al.

Figures

Figure 1
Figure 1
(A) Analysis of blood glucose in mice 2 h after administration of SGLT-2i (Dapagliflozin). There was no difference in blood glucose across groups. n = 34, RM-ANOVA, Sidak multiple comparison test. (B) Comparison of systolic pressure between control and SGLT-2i before and at 2 h after administration of treatments, n = 14, mean ± SEM. *P < 0.05 vs control. ns: P > 0.05 vs control. RM ANOVA, Tukey multiple comparison test. (C) Comparison of diastolic pressure between control and SGLT-2i before and at 2 h after administration of treatments, n = 14, mean ± SEM. *P < 0.05 vs control. ns: P > 0.05 vs control. RM ANOVA, Tukey multiple comparison test. (D) Comparison of heart rate between control and SGLT-2i before and at 2 h after administration of treatments, n = 14, mean ± SEM. ns: P > 0.05 vs control. RM ANOVA, Tukey multiple comparison test.
Figure 2
Figure 2
Grayscale contrast showing expression of SGLT-2 in Telencephalon (A and B); Diencephalon (C and D); Midbrain and Brainstem (E and F). Abbreviations: AOM, medial anterior olfactory region; AOL, anterior olfactory nucleus, lateral part; AOD, anterior olfactory nucleus, dorsal part; AOVP, anterior olfactory nucleus, ventroposterior part; DTT, dorsal tenia tecta layer; E/OV, olfactory ventricle (olfactory part of lateral ventricle); AOP, anterior olfactory nucleus, posterior part; aca, anterior commissure, anterior part; PrL, prelimbic cortex; fmi, forceps minor of the corpus callosum; CPu, caudate putamen (striatum); Nv, navicular nucleus of the basal forebrain; DTT, dorsal tenia tecta; DP, dorsal peduncular cortex; Cg2, cingulate cortex, area 2; LSI, lateral septal nucleus, intermediate part; LSV, lateral septal nucleus, ventral part; LSD, lateral septal nucleus, dorsal part; VDB, nucleus of the vertical limb of the diagonal band; CC, corpus callosum; LSD, lateral septal nucleus, dorsal part; MnPO, median preoptic nucleus; BNST, bed nucleus of the stria terminalis; ac, anterior commissure; LPO, lateral preoptic area; MPA, medial preoptic area; MPO, medial preoptic nucleus; PVA, paraventricular thalamic nucleus, anterior part; PVN, paraventricular hypothalamic nucleus; CM, central medial thalamic nucleus; AM, anteromedial thalamic nucleus; Re, reuniens thalamic nucleus; LH, lateral hypothalamus; RCh, retrochiasmatic area; CA3, field CA3 of the hippocampus; PVA, paraventricular thalamic nucleus, anterior part; PVP, paraventricular thalamic nucleus, posterior part; PV, paraventricular thalamic nucleus; IAM, interanteromedial thalamic nucleus; Re, reuniens thalamus nucleus; PH, posterior hypothalamic nucleus; AHC, anterior hypothalamic area, central part; DMD, dorsomedial hypothalamic nucleus, dorsal part; DM, dorsomedial hypothalamic nucleus; VMH, ventromedial hypothalamic nucleus; VMHVL, ventromedial hypothalamic nucleus, ventrolateral part; Arc, arcuate hypothalamic nucleus; ME, median eminence; ML, medial mammillary nucleus, lateral part; VTM, ventral tuberomammillary nucleus; p1PAG, p1 periaqueductal gray; PrC, precommissural nucleus; PAG, periaqueductal gray; Aq, aqueduct; Pn, pontine nuclei; DCIC, dorsal cortex of the inferior colliculus; DLL, dorsal nucleus of the lateral leminiscus; DRD, dorsal raphe nucleus, dorsal part; PTg, pedunculopontine tegmental nucleus; LPB, lateral parabrachial nucleus; DTgP, dorsal tegmental nucleus, pericentral part; DTgC, dorsal tegmental nucleus, central part; CG, central gray; LC, locus coerules; PDTg, posterodorsal tgmental nucleus; PO, periolivary nucleus; py, pyramidal tract; 4V, 4th ventricle; solitary tract nucleus; Rt, reticular nucleus; AP, area postrema.
Figure 3
Figure 3
Comparison of FOS-IR for nuclei between control and SGLT-2i in telencephalon (A); amygdalar nuclei and hippocampus (B); thalamus (C); hypothalamus (D); midbrain (E); brainstem (F), n = 12, mean ± SEM. *P < 0.05 vs control; ns: no significance; Two-way ANOVA, Sidak multiple comparison test. Abbreviations: BNST, bed nucleus of stria terminalis; MnPO, median preoptic nucleus; LPO, lateral preoptic area; MPO, medial preoptic nucleus; MPA, medial preoptic area; MS, medial septum; Me, medial amygdala nucleus; Ce, central amygdala nucleus; BMA, basomedial amygdala nucleus; BLA, basolateral amygdala nucleus; Pirl, piriform cortex; CA3, field CA3 of the hippocampus; PVA, paraventricular nucleus of thalamus; CM, central medial thalamic nucleus; Rh, rhomboid thalamic nucleus; Re, reuniens thalamic nucleus; IAM, interanteromedial thalamic nucleus; PVN, paraventricular nucleus of hypothalamus; VMH, ventromedial hypothalamus; LH, lateral hypothalamic area; ARC, arcuate nucleus; AHC, anterior hypothalamic nucleus; SC, superior colliculus; PAG, periaqueductal gray; DR, dorsal raphe nucleus; PTg, pedunculopontine tegmental nucleus; VTA, ventral tegmental area; Pn, potine nucleus; AP, area postrema; Sol/NTS, nucleus of solitary tract; Py, pyramidal tract; LC, locus coeruleus; CG, central gray; PO, periolivary nucleus; LPB, lateral parabrachial nucleus; Rt, reticular nucleus.
Figure 4
Figure 4
Analysis of c-Fos expression between SGLT-2i (A, B, C) and control group (D, E, F) in MnPO, PVA, and PVN (A); Superior colliculus, PAG, and LC (B); NTS, CA3, and amygdalar nuclei (C); Scale bar: 100μm. Abbreviations: MnPO, median preoptic nucleus; ac, anterior commissure; PVA, paraventricular thalamic nucleus; D3V, dorsal 3rd ventricle; PVN, paraventricular hypothalamic nucleus; 3V, 3rd ventricle; Aq, aqueduct; PAG, periaqueductal gray; LC, locus coeruleus; 4V, 4th ventricle; NTS, nucleus of solitary tract; AP, area postrema; CC, central canal; CA3, the field CA3 of hippocampus; Me, medial amygdala nucleus; Ce, central amygdala nucleus; BMA, basomedial amygdala nucleus; BLA, basolateral amygdala nucleus; Pirl, piriform cortex.
Figure 5
Figure 5
Continued.
Figure 5
Figure 5
Continued.
Figure 5
Figure 5
(A) c-Fos expression is upregulated in SGLT-2i group (A, B, C, D) vs control group (E, F, G, H) as determined by immunofluorescence assay in MnPO (A); PVA (B); PVN (C); SC (D); PAG (E); LC (F); NTS (G); CA3 (H); Me (I); Red: Alexa Fluor-594, staining showing c-Fos expression in nucleus of neurons; Green: Alexa Fluor-488, staining showing SGLT-2 expression surround nucleus of neurons; Scale bar: 100μm. Magnification: A and E=5X; B, C, D and F, G, H=20X. Abbreviations: MnPO, median preoptic nucleus; ac, anterior commissure; PVA, paraventricular thalamic nucleus; D3V, dorsal 3rd ventricle; PVN, paraventricular hypothalamic nucleus; 3rdV, 3rd ventricle; SC, superior colliculus; Aq, aqueduct; PAG, periaqueductal gray; Aq, aqueduct; LC, locus coeruleus; 4V, 4th ventricle; AP, area postrema; NTS, nucleus of solitary tract; CC, central canal; D3V, dorsal 3rd ventricle; CA3, the field CA3 of hippocampus; Me, medial amygdala nucleus; Ce, central amygdala nucleus; BMA, basomedial amygdala nucleus; BLA, basolateral amygdala nucleus; Pirl, piriform cortex.
Figure 6
Figure 6
Comparison of the known peripheral pathway (black full line) with central pathway proposed in this study (blue dotted line) through which SGLT-2i regulates cardiovascular processes. The list of mechanisms through which SGLT-2 inhibitors improve cardiac function both via peripheral and central pathways. SGLT-2 inhibitors inhibit peripheral reabsorption of sodium and glucose in proximal convoluted tubules (upper left corner) leading to natriuresis and glucosuria. Natriuresis can deplete the plasma volume and increase tubuloglomerular feedback. Reduced glucose reabsorption may result in a decrease in body weight, glyco-toxicity and inflammation accompanied by uricosuria. In terms of central mechanism, SGLT-2 inhibitors may act on cardiovascular regulation related nuclei, such as PVN, NTS, PAG and other nuclei. SGLT-2 inhibitors may eventually act on RVLM to influence the sympathetic flow to IML with sympathetic preganglionic neurons. Eventually, this promotes the parasympathetic nervous activity thereby decreases blood pressure and heart rate. Abbreviations: PVN, paraventricular nucleus of hypothalamus; NTS, nucleus of solitary tract; PAG, periaqueductal gray; RVLM, rostral ventrolateral medulla; IML, intermediolateral nucleus of spinal cord; BP, blood pressure.

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