Empagliflozin demonstrates neuroprotective and cardioprotective effects by reducing ischemia/reperfusion damage in rat models of
Authors:
Journal: Scientific reports
Publication Type: Journal Article
Date: 2025
DOI: PMC11910632
ID: 40089564
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated potential neuroprotective and cardioprotective effects in preliminary studies. This study evaluates the efficacy of empagliflozin (EMPA) in reducing ischemia/reperfusion damage in both the brain and heart using rat models. Ischemic stroke and myocardial infarction (MI) were induced in male Sprague-Dawley rats, which were randomized into three groups: (1) Control (no EMPA), (2) Acute treatment (EMPA, 10 mg/kg IV, administered 10 min before ischemia and 1 min before reperfusion), and (3) Chronic treatment (EMPA, 20 mg/kg in food for 7 days before ischemia). Stroke was induced by middle cerebral artery occlusion (MCAO) for one hour, followed by 3 h of reperfusion, and MI was induced by left coronary artery occlusion for 30 min, followed by 3 h of reperfusion. Brain and heart tissues were analyzed for anatomic size of myocardial infarction and stroke. In the brain, cerebral infarction was significantly smaller in both EMPA treatment groups compared to controls (acute: 3.7 ± 1.2%, chronic: 6.9 ± 2.1% vs. control: 14.5 ± 2.5%, p < 0.05). Edema was also reduced in the EMPA groups (acute: 5.5 ± 0.9%, chronic: 5.9 ± 0.8% vs. control: 9.6 ± 1.2%, p < 0.05). In the heart, MI size was significantly reduced in both EMPA groups (acute: 46.9 ± 2.0%, chronic: 48.8 ± 5.8% vs. control: 70.0 ± 2.6%, p < 0.05), and no-reflow size was smaller in the EMPA groups (acute: 36.3 ± 3.3%, chronic: 33.9 ± 4.3% vs. control: 53.4 ± 3.3%, p < 0.05). EMPA treatment, both acute and chronic, significantly reduces cerebral infarct volume and edema, as well as myocardial infarct size and no-reflow in rat models of ischemic stroke and myocardial ischemia/reperfusion, indicating substantial neuroprotective and cardioprotective effects.
Chemical List
- Glucosides|||Benzhydryl Compounds|||empagliflozin|||Neuroprotective Agents|||Cardiotonic Agents|||Sodium-Glucose Transporter 2 Inhibitors
Reference List
- Seefeldt, J. M. et al. Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats. Sci. Rep.11 (1), 9544 (2021).|||Tavecchia, G. A., Gualini, E., Sacco, A. & Oliva, F. The role of sodium-glucose co-transporter 2 inhibitors in myocardial infarction: available evidence and future perspectives. Eur. Heart J. Suppl.26 (Suppl 1), i84–i87 (2024).|||Al Hamed, F. A. & Elewa, H. Potential therapeutic effects of sodium Glucose-linked cotransporter 2 inhibitors in stroke. Clin. Ther.42 (11), e242–e249 (2020).|||Takashima, M. et al. Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects. Commun. Biol.5 (1), 653 (2022).|||Tsai, W. H. et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci. Rep.11 (1), 15364 (2021).|||Vercalsteren, E. et al. The SGLT2 inhibitor empagliflozin promotes post-stroke functional recovery in diabetic mice. Cardiovasc. Diabetol.23 (1), 88 (2024).|||Connelly, K. A. et al. Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction. Cardiovasc. Diabetol.19 (1), 13 (2020).|||Yaribeygi, H. et al. Sodium glucose Cotransporter-2 inhibitor empagliflozin increases antioxidative capacity and improves renal function in diabetic rats. J. Clin. Med.12 (11), 3815 (2023).|||Kim, S., Jo, C. H. & Kim, G. H. Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats. Hypertens. Res.42 (12), 1905–1915 (2019).|||Sharp, P. & Villano, J. S. The Laboratory Rat. 2nd Edition. Published December 11, by CRC Press. ISBN 9781439829868. (2012).|||Zea Longa, E. L., Weinstein, P. R., Carlson, S. & Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke20, 84–91 (1989).|||Nouraee, C. et al. A brief review of Edema-Adjusted infarct volume measurement techniques for rodent focal cerebral ischemia models with practical recommendations. J. Vasc Interv Neurol.10 (3), 38–45 (2019).|||Reglodi, D. et al. Effects of pretreatment with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia. Peptides23 (12), 2227–2234 (2002).|||Dai, W. & Kloner, R. A. Effects of acetaminophen on myocardial infarct size in rats. J. Cardiovasc. Pharmacol. Ther.8 (4), 277–284 (2003).|||Dai, W. & Kloner, R. A. Experimental cell transplantation therapy in rat myocardial infarction model including nude rat Preparation. In: (ed Lee, R. J.) Stem Cells for Myocardial Regeneration, Methods in Molecular Biology™. Springer; (2010). Volume 660, Part 2, 99–109.|||Piątkowska-Chmiel, I. et al. Molecular and neural roles of sodium-glucose cotransporter 2 inhibitors in alleviating neurocognitive impairment in diabetic mice. Psychopharmacol. (Berl). 240 (4), 983–1000 (2023).|||Bdel-Latif, R. G., Rifaai, R. A. & Amin, E. F. Empagliflozin alleviates neuronal apoptosis induced by cerebral ischemia/reperfusion injury through HIF-1α/VEGF signaling pathway. Arch. Pharm. Res.43, 514–525 (2020).|||Amin, E. F., Rifaai, R. A. & Abdel-Latif, R. G. Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative-inflammatory-apoptotic pathway. Fundam Clin. Pharmacol.34 (5), 548–558 (2020).|||Kunz, A. & Iadecola, C. Cerebral vascular dysregulation in the ischemic brain. Handb. Clin. Neurol.92, 283–305 (2009).|||Lee, S. Y. et al. Sodium/glucose Co-Transporter 2 inhibitor, Empagliflozin, alleviated transient expression of SGLT2 after myocardial infarction. Korean Circ. J.51 (3), 251–262 (2021).|||Cai, C. et al. Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway. Redox Biol.52, 102288 (2022).|||Lu, Q. et al. Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway. Mol. Cell. Endocrinol.501, 110642 (2020).|||Lahnwong, S. et al. Acute Dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc. Diabetol.19 (1), 91 (2020).|||Sayour, A. A. et al. Acute Canagliflozin treatment protects against in vivo myocardial ischemia/reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation. J. Transl Med.17 (1), 127 (2019).|||Lopaschuk, G. D. & Verma, S. Mechanisms of cardiovascular benefits of sodium glucose Co-Transporter 2 (SGLT2) inhibitors: A State-of-the-Art review. JACC Basic. Transl Sci.5 (6), 632–644 (2020).|||Durante, W., Behnammanesh, G. & Peyton, K. J. Effects of Sodium-Glucose Co-Transporter 2 inhibitors on vascular cell function and arterial remodeling. Int. J. Mol. Sci.22 (16), 8786 (2021).|||Kloner, R. A. Stunned and hibernating myocardium: where are we nearly 4 decades later?? J. Am. Heart Assoc.9 (3), e015502 (2020).|||Htoo, P. T. et al. Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study. Cardiovasc. Diabetol.23 (1), 57 (2024).|||Rivera, F. B. et al. Sex differences in cardiovascular outcomes of SGLT-2 inhibitors in heart failure randomized controlled trials: A systematic review and meta-analysis. Am. Heart J. Plus. 26, 100261 (2023).|||Li, Y. & Kloner, R. A. The cardioprotective effects of ischemic ‘preconditioning’ are not mediated by adenosine receptors in rat hearts. Circulation87 (5), 1642–1648 (1993).|||Dow, J. & Kloner, R. A. Postconditioning does not reduce myocardial infarct size in an in vivo regional ischemia rodent model. J. Cardiovasc. Pharmacol. Ther.12 (2), 153–163 (2007).|||Quentin, V., Singh, M. & Nguyen, L. S. A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena. World J. Diabetes. 13 (9), 683–695 (2022).|||Ravendran, K. et al. The use of empagliflozin post myocardial infarction. Cureus15 (6), e40602 (2023).|||Sysoev, Y. I. et al. Changes in brain electrical activity after transient middle cerebral artery occlusion in rats. Neurol. Int.14 (3), 547–560 (2022).|||Liu, P. et al. Electrophysiological signatures in global cerebral ischemia: neuroprotection via chemogenetic Inhibition of CA1 pyramidal neurons in rats. J. Am. Heart Assoc.13 (24), e036146 (2024).|||Amini, N. et al. Improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal Ischemia-Reperfusion injury. Arq. Bras. Cardiol.117 (2), 290–297 (2021).