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Original Research

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

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Pages 2781-2799 | Published online: 05 Aug 2020

References

  • Sobel BE, Schneider DJ. Cardiovascular complications in diabetes mellitus. Curr Opin Pharmacol. 2005;5:143–148. doi:10.1016/j.coph.2005.01.002
  • Valensi P, Prevost G. CVOTs: what did the endocrinologist learn? Diabetes Res Clin Pract. 2019;107947. doi:10.1016/j.diabres.2019.107947
  • Dewan P, Solomon SD, Jhund PS, et al. Efficacy and safety of sodium–glucose co-transporter2 inhibition according to left ventricular ejection fraction in DAPA-HF. Eur J Heart Fail. 2020. doi:10.1002/ejhf.1867
  • Salman IM. Major autonomic neuroregulatory pathways underlying short- and long-term control of cardiovascular function. Curr Hypertens Rep. 2016;18(18). doi:10.1007/s11906-016-0625-x
  • de Kloet AD, Liu M, Rodriguez V, Krause EG, Sumners C. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control. Am J Physiol Regul Integr Comp Physiol. 2015;309:R444–458. doi:10.1152/ajpregu.00078.2015
  • Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clinic Proceedings. 1993;68:988–1001. doi:10.1016/s0025-6196(12)62272-1
  • Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752–772. doi:10.1161/CIRCULATIONAHA.116.021887
  • Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–794. doi:10.1152/physrev.00055.2009
  • Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–275 e269. doi:10.1016/j.jash.2014.01.007
  • Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–476. doi:10.1016/j.jjcc.2017.12.004
  • Sawada Y, Izumida Y, Takeuchi Y, et al. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry. Biochem Biophys Res Commun. 2017;493:40–45. doi:10.1016/j.bbrc.2017.09.081
  • Chiba Y, Yamada T, Tsukita S, et al. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PLoS One. 2016;11:e0150756. doi:10.1371/journal.pone.0150756
  • Szablewski L. Glucose transporters in brain: in health and in Alzheimer’s disease. J Alzheimers Dis. 2017;55:1307–1320. doi:10.3233/JAD-160841
  • Koekkoek LL, Mul JD, la Fleur SE. Glucose-sensing in the reward system. Front Neurosci. 2017;11:716. doi:10.3389/fnins.2017.00716
  • Chen LQ, Cheung LS, Feng L, Tanner W, Frommer WB. Transport of sugars. Annu Rev Biochem. 2015;84:865–894. doi:10.1146/annurev-biochem-060614-033904
  • Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer. 2005;41:2449–2461. doi:10.1016/j.ejca.2005.08.008
  • Sagar SM, Sharp FR, Curran T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science. 1988;240:1328–1331. doi:10.1126/science.3131879
  • Morgan JI, Curran T. Stimulus-transcription coupling in neurons: role of cellular immediate-early genes. Trends Neurosci. 1989;12:459–462. doi:10.1016/0166-2236(89)90096-9
  • Patel DK, Strong J. The Pleiotropic effects of sodium-glucose cotransporter-2 inhibitors: beyond the glycemic benefit. Diabetes Ther. 2019;10:1771–1792. doi:10.1007/s13300-019-00686-z
  • Chilton RJ. Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes. Diabetes Obes Metab. 2020;22:16–29. doi:10.1111/dom.13854
  • Matthews VB, Elliot RH, Rudnicka C, et al. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059–2068. doi:10.1097/HJH.0000000000001434
  • Jordan J, Tank J, Heusser K, et al. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J Am Soc Hypertens. 2017;11:604–612. doi:10.1016/j.jash.2017.07.005
  • Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85(5):520–526. doi:10.1038/clpt.2008.251
  • Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014;53:17–27. doi:10.1007/s40262-013-0104-3
  • Sabolic I, Vrhovac I, Eror DB, et al. Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol. 2012;302:C1174–C1188. doi:10.1152/ajpcell.00450.2011
  • Yu AS, Hirayama BA, Timbol G, et al. Regional distribution of SGLT activity in rat brain in vivo. Am J Physiol Cell Physiol. 2013;304:C240–C247. doi:10.1152/ajpcell.00317.2012
  • Vemula S, Roder KE, Yang T, et al. A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther. 2009;328:487–495. doi:10.1124/jpet.108.146589
  • Erdogan MA, Yusuf D, Christy J, et al. Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy. BMC Neurol. 2018;18:81. doi:10.1186/s12883-018-1086-4
  • Gong M, Wen S, Nguyen T, et al. Converging relationships of obesity and hyperuricemia with special reference to metabolic disorders and plausible therapeutic implications. Diabetes Metab Syndr Obes. 2020;13:943–962. doi:10.2147/dmso.s232377
  • Naznin F, Sakoda H, Okada T, et al. Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice. Eur J Pharmacol. 2017;794:37–44. doi:10.1016/j.ejphar.2016.11.028
  • Sa-Nguanmoo P, Tanajak P, Kerdphoo S, et al. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol. 2017;333:43–50. doi:10.1016/j.taap.2017.08.005
  • Dampney RAL, Horiuchi J. Functional organisation of central cardiovascular pathways: studies using c-fos gene expression. Prog Neurobiol. 2003;71:359–384. doi:10.1016/j.pneurobio.2003.11.001
  • Hoffman GE, Smith MS, Verbalis JG. c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol. 1993;14:173–213. doi:10.1006/frne.1993.1006
  • Dragunow M, Faull R. The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods. 1989;29:261–265. doi:10.1016/0165-0270(89)90150-7
  • Kovacs KJ. Measurement of immediate-early gene activation- c-fos and beyond. J Neuroendocrinol. 2008;20:665–672. doi:10.1111/j.1365-2826.2008.01734.x
  • Galosy RA, Clarke LK, Vasko MR, Crawford IL. Neurophysiology and neuropharmacology of cardiovascular regulation and stress. Neurosci Biobehav Rev. 1981;5:137–175. doi:10.1016/0149-7634(81)90040-3
  • Zhou L, Podolsky N, Sang Z, et al. The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemia. Diabetes. 2010;59(10):2646–2652. doi:10.2337/db09-0995
  • Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51(5):1145–1149. doi:10.1021/jm701272q
  • Ems R, Garg A, Ostergard TA, Miller JP. Potential deep brain stimulation targets for the management of refractory hypertension. Front Neurosci. 2019;13:93. doi:10.3389/fnins.2019.00093
  • Kasher N, Wittbrodt MT, Alam ZS, et al. Sex differences in brain activation patterns with mental stress in patients with coronary artery disease. Biol Sex Differ. 2019;10:35. doi:10.1186/s13293-019-0248-4
  • Valenza G, Sclocco R, Duggento A, et al. The central autonomic network at rest: uncovering functional MRI correlates of time-varying autonomic outflow. NeuroImage. 2019;197:383–390. doi:10.1016/j.neuroimage.2019.04.075
  • Bremner JD, Campanella C, Khan Z, et al. Brain correlates of mental stress-induced myocardial ischemia. Psychosom Med. 2018;80:515–525. doi:10.1097/PSY.0000000000000597
  • Shoemaker JK, Norton KN, Baker J, Luchyshyn T. Forebrain organization for autonomic cardiovascular control. Auton Neurosci. 2015;188:5–9. doi:10.1016/j.autneu.2014.10.022
  • Templin C, Hänggi J, Klein C, et al. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. Eur Heart J. 2019;40(15):1183–1187. doi:10.1093/eurheartj/ehz068
  • Wen S, Wang C, Gong M, Zhou L. An overview of energy and metabolic regulation. Sci China Life Sci. 2019;62:771–790. doi:10.1007/s11427-018-9371-4
  • Morrison SF, Nakamura K. Central mechanisms for thermoregulation. Annu Rev Physiol. 2019;81:285–308. doi:10.1146/annurev-physiol-020518-114546
  • Walker WH, Walton JC, DeVries AC, Nelson RJ. Circadian rhythm disruption and mental health. Transl Psychiatry. 2020;10:28. doi:10.1038/s41398-020-0694-0
  • Abreu AP, Toro CA, Song YB, et al. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. J Clin Invest. 2020. doi:10.1172/JCI136564
  • Carmichael CY, Wainford RD. Hypothalamic signaling mechanisms in hypertension. Curr Hypertens Rep. 2015;17:39. doi:10.1007/s11906-015-0550-4
  • Coote JH, Yang Z, Pyner S, Deering J. Control of sympathetic outflows by the hypothalamic paraventricular nucleus. Clin Exp Pharmacol Physiol. 1998;25:461–463. doi:10.1111/j.1440-1681.1998.tb02235.x
  • Alon T, Zhou L, Pérez CA, et al. Transgenic mice expressing green fluorescent protein under the control of the corticotropin-releasing hormone promoter. Endocrinology. 2009;150(12):5626–5632. doi:10.1210/en.2009-0881
  • McKinley MJ, Yao ST, Uschakov A, et al. The median preoptic nucleus: front and centre for the regulation of body fluid, sodium, temperature, sleep and cardiovascular homeostasis. Acta Physiologica. 2015;214(8–32):8–32. doi:10.1111/apha.12487
  • Zhou L, Sutton GM, Rochford JJ, et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6(5):398–405. doi:10.1016/j.cmet.2007.10.008
  • Rossi F, Maione S, Berrino L. Periaqueductal gray area and cardiovascular function. Pharmacol Res. 1994;29:27–36. doi:10.1016/1043-6618(94)80095-2
  • Potts JT, Spyer KM, Paton JF. Somatosympathetic reflex in a working heart-brainstem preparation of the rat. Brain Res Bull. 2000;53:59–67. doi:10.1016/s0361-9230(00)00309-9
  • Owens NC, Verberne AJ. Medial prefrontal depressor response: involvement of the rostral and caudal ventrolateral medulla in the rat. J Auton Nerv Syst. 2000;78:86–93. doi:10.1016/s0165-1838(99)00062-4
  • Howe PR. Blood pressure control by neurotransmitters in the medulla oblongata and spinal cord. J Auton Nerv Syst. 1985;12(2–3):95–115. doi:10.1016/0165-1838(85)90054-2
  • Ito S, Sved AF. Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats. Am J Physiol. 1997;273:R1657–R1662. doi:10.1152/ajpregu.1997.273.5.R1657
  • Park JH, Gorky J, Ogunnaike B, Vadigepalli R, Schwaber JS. Investigating the effects of brainstem neuronal adaptation on cardiovascular homeostasis. Front Neurosci. 2020;14:470. doi:10.3389/fnins.2020.00470
  • Grassi G, Dell’Oro R, Quarti-Trevano F, et al. Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia. 2005;48:1359–1365. doi:10.1007/s00125-005-1798-z
  • Elliott RH, Matthews VB, Rudnicka C, Schlaich MP. Is it time to think about the sodium glucose co-transporter 2 sympathetically? Nephrology. 2016;21:286–294. doi:10.1111/nep.12620
  • Joca HC, Santos‐Miranda A, Joviano-Santos JV, et al. Chronic sympathetic hyperactivity triggers electrophysiological remodeling and disrupts excitation-contraction coupling in heart. Sci Rep. 2020;10(1):8001. doi:10.1038/s41598-020-64949-7
  • Gronda E, Vanoli E, Sacchi S, et al. Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options. Heart Fail Rev. 2020;25(2):295–303. doi:10.1007/s10741-019-09823-z
  • Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20:479–487. doi:10.1111/dom.13126
  • Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 2016;42:224–233. doi:10.1016/j.diabet.2016.05.006